Subthalamic Neuronal Firing in Obsessive-Compulsive Disorder and Parkinson Disease

Article (PDF Available)inAnnals of Neurology 69(5):793-802 · May 2011with54 Reads
DOI: 10.1002/ana.22222 · Source: PubMed
Abstract
Although electrophysiologic dysfunction of the subthalamic nucleus is putative, deep brain stimulation of this structure has recently been reported to improve obsessions and compulsions. In Parkinson disease, sensorimotor subthalamic neurons display high-frequency burst firing, which is considered as an electrophysiologic signature of motor loop dysfunction. We addressed whether such neuronal dysfunction of the subthalamic nucleus also exists in the nonmotor loops involved in patients with obsessive-compulsive disorder. We compared the neuronal activity of the subthalamic nucleus recorded in 9 patients with obsessive-compulsive disorder with that of 11 patients with Parkinson disease measured during intraoperative exploration for deep brain stimulation. The mean subthalamic neuron discharge rate was statistically lower in patients with obsessive-compulsive disorder than in patients with Parkinson disease (20.5 ± 11.0 Hz, n = 100 and 30.8 ± 15.6 Hz, n = 93, respectively, p < 0.001). The relative proportion of burst neurons did not differ significantly between the 2 diseases (75% vs 73%). Interestingly, burst neurons were predominantly left-sided in obsessive-compulsive disorder. The recording of burst neurons within the nonmotor subthalamic nucleus in patients with obsessive-compulsive disorder is a novel finding that suggests the existence of deregulation of the nonmotor basal ganglia loop, possibly left-sided. Potentially, burst activity might interfere with normal processes occurring within nonmotor loops.
ORIGINAL ARTICLE
Subthalamic Neuronal Firing in Obsessive-
Compulsive Disorder and
Parkinson Disease
Brigitte Piallat, PhD,
1,2
Mircea Polosan, MD,
2,3
Vale
´
rie Fraix, MD, PhD,
1,2,4
Laurent Goetz, MSc,
2
Olivier David, PhD,
1,5
Albert Fenoy, MD,
2
Napoleon Torres, MD, PhD,
8
Jean-Louis Quesada, MSc,
1,7
Eric Seigneuret, MD,
2,6
Pierre Pollak, MD,
1,2,4
Paul Krack, MD, PhD,
1,2,4
Thierry Bougerol, MD,
1,3
Alim L. Benabid, MD, PhD,
1,8
and Ste
´
phan Chabarde
`
s, MD
1,2,6
Objective: Although electrophysiologic dysfunction of the subthalamic nucleus is putative, deep brain stimulation of
this structure has recently been reported to improve obsessions and compulsions. In Parkinson disease, sensorimotor
subthalamic neurons display high-frequency burst firing, which is considered as an electrophysiologic signature of
motor loop dysfunction. We addressed whether such neuronal dysfunction of the subthalamic nucleus also exists in
the nonmotor loops involved in patients with obsessive-compulsive disorder.
Methods: We compared the neuronal activity of the subthalamic nucleus recorded in 9 patients with obsessive-
compulsive disorder with that of 11 patients with Parkinson disease measured during intraoperative exploration for
deep brain stimulation.
Results: The mean subthalamic neuron discharge rate was statistically lower in patients with obsessive-compulsive
disorder than in patients with Parkinson disease (20.5 6 11.0 Hz, n ¼ 100 and 30.8 6 15.6 Hz, n ¼ 93, respectively,
p < 0.001). The relative proportion of burst neurons did not differ significantly between the 2 diseases (75% vs 73%).
Interestingly, burst neurons were predominantly left-sided in obsessive-compulsive disorder.
Interpretation: The recording of burst neurons within the nonmotor subthalamic nucleus in patients with obsessive-
compulsive disorder is a novel finding that suggests the existence of deregulation of the nonmotor basal ganglia
loop, possibly left-sided. Potentially, burst activity might interfere with normal processes occurring within nonmotor
loops.
ANN NEUROL 2010;00:000–000
O
bsessive-compulsive disorder (OCD) is a relatively
common psychiatric disease, affecting 2 to 3% of
the population.
1
It is characterized by recurrent
unwanted ideas, images, or impulses (obsessions), and re-
petitive stereotyped behaviors or mental acts (compul-
sions), often intended to neutralize the anxiety induced
by the obsessions. Despite pharmacologic treatment and
cognitive behavioral therapy, approximately 20% of
patients with OCD remain severely disabled.
1
Several
lines of evidence support the concept that OCD pathoge-
nesis may result from dysfunction in the frontobasal gan-
glia-thalamocortical loops, because OCD symptoms have
been documented in various diseases involving striatal
dysfunction,
2,3
and neuroimaging of OCD has shown
significant structural and functional abnormalities within
the orbitofrontal cortex and the striatum, which partly
respond to pharmacologic and cognitive behavioral ther-
apy.
4–6
The subthalamic nucleus (STN), a key structure
View this article online at wileyonlinelibrary.com. DOI: 10.1002/ana.22222
Received Mar 29, 2010, and in revised form Aug 4, 2010. Accepted for publication Aug 6, 2010.
Address correspondence to Pr Chabarde
`
s, Grenoble Institut des Neurosciences, INSERM-U836, Equipe 11, Universite
´
Joseph Fourier, Site Sante, La
Tronche, BP170, 38042 Grenoble ce
´
dex 9, France. E-mail: SChabardes@chu-grenoble.fr
From the
1
Grenoble University, France;
2
INSERM-U836, Grenoble Institute of Neurosciences, France;
3
Department of Psychiatry,
4
Department of Neurology,
5
Department of Neuroradiology,
6
Department of Neurosurgery,
7
Center of Clinical Investigation and INSERM-003, University Hospital of Grenoble, France;
8
Atomic Energy Commission of Grenoble, France.
Additional Supporting Information may be found in the online version of this article.
V
C
2010 American Neurological Association 1
of the frontobasal ganglia-thalamocortical motor loop,
also seems crucial for the nonmotor (noM) parallel
loops that are involved in the emotional and cognitive
components of behavior.
7,8
Furthermore, acute STN
deep brain stimulation (DBS) can induce mood changes
in patients with Parkinson disease (PD),
9
supporting
the role of STN in emotional behavior. In monkeys,
anatomic studies have shown that the cortical areas
involved in motor, cognitive, and emotional functions
are processed in distinct territories within the STN
10
;a
large dorsolateral area receives sensorimotor (SM) input
and a noM area, encompassing ventromedial and ante-
romedial parts, receives associative and limbic system
inputs, respectively.
Lesional surgery or DBS of the cingulum,
11
the ante-
rior capsule,
12,13
thesubcaudatetract,
14
the limbic sys-
tem,
15
and the nucleus accumbens
16
have been considered
as therapeutic options in patients with OCD. Recently, the
DBS in OCD study group (ST OC) found that STN-DBS
markedly improved OCD symptoms.
17
However , the sub-
strate of the involvement of the STN in OCD remains
unknown. In patients with PD and in monkeys rendered
parkinsonian, clinical efficacy of STN-DBS suggests the
key role of SM-STN in the pathophysiology of motor
symptoms.
18
Furthermore, the depletion of striatal dopa-
mine is related to changes in the firing rate (FR) and pat-
tern of STN neurons that become hyperactive, exhibiting
burst activity
19–23
and potentially contributing to the
appearance of motor symptoms. If cognitive or emotional
loops are involved in OCD, an electrophysiologic signature
should be found in the noM-STN as well. To address this
hypothesis, we compared the electrophysiologic properties
of noM-STN neurons in patients with OCD to those of
SM-STN neurons in patients with PD.
Patients and Methods
Participants
Ten patients with OCD were initially recruited for this study,
but 1 was excluded because microrecordings were not amenable
to analysis. Ultimately, 7 women and 2 men with OCD, aged
34 to 52 years (mean, 39.5 6 5.5 years), and 3 women and 8
men with PD, aged 28 to 68 years (mean, 54.3 6 15.3 years)
were included in the study. We retrospectively analyzed data
gathered during routine microrecording performed for the im-
plantation of DBS leads into the STN, using the same proce-
dures conducted at the University Hospital of Grenoble
18
for
the last 17 years. Patients with OCD were all referred to our
center after unsuccessful medical and cognitive behavioral
TABLE 1: Clinical Characteristics of Patients with Obsessive-Compulsive Disorder at Time of Surgery
Patient
Number Sex
Age,
yr
Duration of
Symptoms,
yr YBOCS GAF CGI
Medication, Total Daily Dose, mg
SNRI and SRI FGA and SGA Other
Medications
O1 M 39 18 18þ19 26 6 Fluvoxamine 200 Pimozide 1 Clonidine 0.3
O2 F 43 32 14þ18 32 6 Sertraline 100 Risperidone 4 Alprazolam 0.75
O3 F 42 25 15þ15 36 5 Fluoxetine 60,
venlafaxine 50
Levomepromazine
25
Bromazepam 6
O4 F 34 24 17þ17 39 5 Escitalopram 30 Clobazam 5;
lamotrigine 75;
mianserin 20
O5 F 35 15 14þ15 36 6 Paroxetine 60
O6 F 37 5 14þ18 33 6 Venlafaxine 150 Bromazepam 9,
hydroxyzine 25
O7 F 52 25 20þ20 33 6 Citalopram 20,
clomipramine 50
Cyamemazine 50 Clobazam 20,
hydroxyzine 200
O8 F 38 11 18þ18 32 6 Sertraline 100 Clonazepam 2
O9 M 36 17 17þ15 40 5 Paroxetine 40
YBOCS scores range from 0 to 40, with higher scores indicating worse function. The 2 YBOCS subscores (obsession þ compul-
sion) range from 0 to 20. GAF scores range from 1 to 90, with higher scores indicating the normal global functional status. CGI
scores range from 1 to 7, with higher scores indicating the severity of the disease.
YBOCS ¼ Yale-Brown Obsessive Compulsive Scale; GAF ¼ Global Assessment of Functioning; CGI ¼ Clinical Global Impres-
sion; SNRI ¼ serotonin and norepinephrine reuptake inhibitors; SRI ¼ serotonin reuptake inhibitors; FGA ¼ first-generation
antipsychotics; SGA, second-generation antipsychotics.
ANNALS of Neurology
2 Volume 000, No. 000
therapy. All patients gave informed consent. We followed strict
ethical guidelines given by the Comite
´
Consultatif National
d’E
´
thique,
24
and we applied established inclusion criteria for
DBS in OCD.
17
Tables 1 and 2 summarize the clinical characteristics of
patients. For patients with OCD, all right-handed, the primary
diagnosis was based on the Diagnostic and Statistical Manual of
Mental Disorders-IV criteria. The Yale-Brown Obsessive Com-
pulsive Scale
25
score was >25, the Global Assessment Function-
ing was <45, and the Clinical Global Impression (severity) was
>4. All 9 patients with OCD were resistant to adequate drug
trials (>12 weeks at the maximum tolerated dose) including at
least 3 serotonin reuptake inhibitors, clomipramine and lith-
ium, clonazepam, and buspirone and pimozide, and at least 1
year of well-conducted cognitive behavioral therapy. Patients
were referred for bilateral STN-DBS electrode implantation.
Three patients were also included in the recent French prospec-
tive study on bilateral STN-DBS for OCD (STOC study).
17
With the exception of 1 patient (O1) who suffered from
comorbid Tourette syndrome and another patient (O2) with a
very mild akinesia as a side effect of neuroleptic treatment
(Unified Parkinsons Disease Rating Scale [UPDRS] part III ¼
3/108), patients with OCD did not suffer from PD or abnor-
mal movements (UPDRS part III ¼ 0/108).
For patients with PD, the mean disease duration was
>10 years. The mean motor UPDRS off-state was 45.4 6
15.3/108. All PD patients suffered from motor complications
of dopaminergic treatment (see Table 2; mean L-dopa equiva-
lent daily dose of 1,302.0 6 658.4mg/d; mean UPDRS items
32 þ 33 was 3.2 6 1.6/8). They did not suffer from severe
cognitive impairment, defined objectively by scores >130/144
on the Mattis dementia rating scale score. Medical treatment
was withheld for at least 12 hours before surgery.
Surgery and Targeting
Targeting was based on stereotactic T1 and T2 magnetic reso-
nance imaging scans fused with televentriculography (Fig 1;
Supporting Information).
26
In patients with PD, the SM-STN was targeted: 6/12 of the
anterior-posterior commissural (AC-PC) length posterior to the
AC, 12mm lateral to the midline, and 3mm below the AC-PC line.
In patients with OCD, the presumed noM-STN was targeted 2mm
anterior and 1mm medial to the previous target. It was then
adjusted during surgical implantation by using multiunit recordings
with 5 microelectrodes. In patients with PD, the SM-STN was
identified as the region in which neurons responded to passive or
active movements and where microstimulation induced improve-
ment of rigidity or tremor or both. Based on that definition, the
most anterior microelectrode was called the noM microelectrode,
because it explored the presumed noM-STN. In patients with
OCD, the noM-STN was identified by the lack of neuronal
responses to passive or active movements and by the lack of SM
side effects such as contralateral paresthesias or motor contractions
induced by microstimulations. In patients with OCD, the most
posterior microelectrode was called the SM microelectrode,becauseit
explored the presumed SM-STN (see F ig 1D).
Microrecording Sessions and Offline Analysis
Under local anesthesia, 5 microelectrodes (2mm apart) were
lowered into the brain using a motorized microdrive (Alpha-
Omega, Nazareth, Israel) on a stereotactic robotic arm (Neuro-
mate, Schaerer-Mayfield, Bron, France). Single-unit events were
discriminated offline using template-matching spike-sorting
software (Spike 2, CED, Cambridge, United Kingdom).
27
The
average neuronal FR was first calculated. Second, neurons were
classified as bursts or irregular as follows. Burst activity showed
a wide or bimodal interval interspike distribution and a
TABLE 2: Clinical Characteristics of Patients with Parkinson Disease at Time of Surgery
Patient
Number
Sex Age, yr Duration of
Symptoms, yr
UPDRS
Motor Score
Off Medication
UPDRS
(item 32 1 33)
L-dopa
Equivalent
Daily Dosage, mg
P1 M 57 18 69 1 3,000
P2 F 66 12 52 4 384
P3 M 54 7 27 5 1,060
P4 M 52 8 40 0 1,390
P5 M 68 14 37 4 860
P6 M 28 3 28 4 1,200
P7 F 61 13 43 4 1,495
P8 M 48 9 60 4 1,350
P9 M 56 9 26 2 1,084
P10 M 60 14 64 5 900
P11 F 48 13 54 3 1,600
UPDRS ¼ Unified Parkinsons Disease Rating Scale.
Piallat et al: STN Firing in OCD and PD
Month, 2010 3
significant single peak on the autocorrelation function
28
(Fig
2A, B). Irregular activity was characterized by a wide interval
interspike distribution and a flat autocorrelogram (see Fig
2C).
28,29
The Supporting Information provides details.
Radiographic Assessment of Microelectrode
Positions and 3-Dimensional Reconstruction
of Recording Sites
Microelectrodes were localized at the beginning and end of the
trajectory using a flat detector-based x-ray system (BioScan,
Geneva, Switzerland) that allowed the 3-dimensional (3-D)
reconstruction of the trajectory of each microelectrode, in rela-
tion to the ventricular landmarks (AC, PC, height of the thala-
mus). The x (anteroposterior), y (lateral), and z (depth) coordi-
nates of each recording site were calculated based on the
distance covered with the microdrive and the corresponding 3-
D trajectory. They were then normalized in the bicommissural
system and plotted into the Morel stereotactic atlas.
30
Statistical Analysis
Statistical analyses were performed using Prism (GraphPad Soft-
ware, La Jolla, CA). Quantitative data were summarized as
mean 6 standard deviation or median and the 25th and 75th
percentiles. The Mann-Whitney U test was used to compare
continuous data. Chi-square analysis was used to test for the
association between the proportion of burst neurons and the
diseases, the hemispheres, and the SM/noM-STN in OCD and
PD. Therefore, p values were Bonferroni corrected for multiple
testing of 5 proportions of burst neurons. The level of signifi-
cance for all statistical tests was defined as p < 0.05 (2-tailed).
Results
FRs and Firing Patterns
We recorded 193 cells (OCD, n ¼ 100; PD, n ¼ 93).
The mean recording duration was 72.4 seconds, with a
mean of 1585 events. The mean FR in OCD was signifi-
cantly lower than that in PD (20.5 6 11.0Hz vs 30.8 6
15.6Hz, respectively, p < 0.001; Fig 3A). Burst and
irregular STN neurons were clearly identified (see Fig 2)
in proportions that did not differ significantly between
OCD and PD (p ¼ 0.76; see Fig 3B). Most neurons in
OCD and PD exhibited burst firing (75% and 73%,
respectively; see Fig 3B). In OCD, the proportion of
burst neurons recorded within the noM-STN reached
83% and was significantly higher than the proportion of
burst neurons recorded by the SM microelectrode (50%,
p ¼ 0.02 after Bonferroni correction). Conversely, in
FIGURE 1: (A) Schematic representation of the sensorimotor
(SM)-subthalamic nucleus (STN) target used for Parkinson
disease (PD) surgery (blue spot) and the nonmotor (noM)-STN
target used for obsessive-compulsive disorder (OCD) (red
spot). Targets are plotted onto a coronal T2 magnetic
resonance imaging (MRI) scan superimposed with an
anteroposterior x-ray ventriculogram. The same targets are
represented on a parasagittal T1 MRI scan (B) and a lateral
x-ray ventriculogram (C). (D) Schema of the position of the 5
microelectrodes used for neuronal recording in the noM-
STN (red part) and the SM-STN (blue part) reported on the
corresponding horizontal section of the Morel stereotactic
atlas. Note that the noM microelectrode explored the noM-
STN in patients with PD and that the SM microelectrode
explored the SM-STN in patients with OCD. The target used
for OCD is 1mm medial and 2mm anterior to that used for
PD. AC 5 anterior commissure; PC 5 posterior commissure;
RN 5 red nucleus.
3
ANNALS of Neurology
4 Volume 000, No. 000
PD, the proportion of burst neurons recorded from the
SM-STN reached 81% and was higher than the propor-
tion of burst neurons recorded with the noM microelec-
trode (55%, p ¼ 0.05 after Bonferroni correction). The
burst characteristics differed significantly between OCD
and PD (Table 3). Burst duration was significantly lower
and the number of spikes per burst was higher in PD as
compared to OCD, and intraburst frequen cy was signifi-
cantly higher in PD than in OCD.
Lateralization of Neuronal Activity
Because of targeting strategy, recorded neurons in
patients with PD were mostly located in the dorsolateral
part, whereas those recorded in patients with OCD were
more ventral, medial, and anterior. In patients with PD,
burst neurons were distributed symmetrically and homo-
genously (70% in the right and 75% in the left side,
p ¼ 0.64; see Figs 3C and 4). In patients with OCD,
burst neurons were located in the ventromedial part of
the STN in an asymmetrical distribution, with 55/66
(83%) burst neurons on the left side compared to 20/34
(59%) on the right side (p ¼ 0.03 after Bonferroni cor-
rection). The mean FR of irregular and burst neurons
did not differ significantly between left and right sides
(all OCD, 22.2 6 11.4Hz right vs 19.6 6 10.7Hz left,
p ¼ 0.25; all PD, 31.4 6 15.9Hz right vs 29.9 6
15.3Hz left, p ¼ 0.53; burst OCD, 22.4 6 12.1Hz right
vs 19.3 6 10.8Hz left, p ¼ 0.35; burst PD, 29.2 61
3.6Hz right vs 30.8 6 4.9Hz left, p ¼ 0.76).
Discussion
From intraoperative recordings performed during DBS
implantation, we report here the properties of STN neu-
rons in patients with severe OCD compared to patients
with PD. Three main characteristics distinguished OCD
from PD neurons: (1) a lower spontaneous FR, (2) a
burst pattern with a lower intraburst frequency, and (3) a
left-sided burst distribution. Although these neurons
were not recorded in the same STN subdivisions, these
electrophysiologic findings suggest noM-STN dysfunc-
tion in OCD.
FR and Firing Pattern
In line with previous studies,
19–22,31,32
we observed a
high incidence of burst activity in PD. We measured a
mean FR of 30Hz, which is lower than the ranges of 33
to 65Hz already reported, possibly because of our more
restrictive methodology for spike detection (see Support-
ing Information). It remained, however, above values
reported in normal monkeys
33
(19Hz) and in patients
with essential tremor
22
(19Hz), which are considered as
nonparkinsonian controls. The way by which we proc-
essed PD data is thus validated by the knowledge that
dopamine depletion significantly increases neuronal FR
along with the development of abnormal burst patterns
23
FIGURE 2: Example of electrophysiologic characteristics of
subthalamic nucleus neurons from patients with obsessive
compulsive disorder (OCD) and Parkinson’s Disease (PD).
The sorted spikes are displayed above the spike train with
burst detection displayed only for burst neurons. The raw
data, interval interspike (ISI) histograms, and
autocorrelograms (AC) are displayed beneath the spike
train. The firing patterns were determined on the basis of
ISI and AC, calculated for 1 second (1-millisecond bin
width). The AC confidence intervals (5% and 95%) were
calculated with the null assumption that the number of
spikes in any bin in the histogram should fit an independent
Poisson process. Burst neurons were characterized by a
wide or bimodal ISI distribution and by a significant single
peak on the AC in patients (A) with PD and (B) with OCD
(C) Irregular firing (obtained from patient with OCD) was
characterized by a wide ISI distribution and a flat AC.
Piallat et al: STN Firing in OCD and PD
Month, 2010 5
in the STN.
34
Interestingly, in OCD, the mean FR of
STN neurons (20Hz) was significantly lower than that in
PD patients (by 55%) and similar to assumed normal
values reported in the above-referenced movement disor-
ders studies (19Hz).
22,33
However, in the absence of con-
trol data and animal models of OCD, it is difficult to
firmly conclude whether the mean FR in patients with
OCD is normal. Nonetheless, an increased mean FR is
unlikely, because no dopaminergic depletion occurs in
OCD. Conversely, the possibility that the lower mean
FR in OCD is due to a regional effect is also not sup-
ported by our data, which did not show any anatomic
differences in mean FR along the 5 microelectrodes that
sampled large portions of SM-STN in OCD and of
noM-STN in PD. This is in accordance with a recent
study in which no correlation between the recording site
and the FR was found in patients with PD using com-
plete mapping of the STN, from 0 to 7mm below AC-
PC and from 9 to 15mm lateral relative to the midline.
22
In addition, no regional difference in FR was reported in
a study largely sampling the STN in parkinsonian mon-
keys (disease induced with 1-methyl-2-phenyl-1,2,3,6-tet-
rahydropyridine) and normal monkeys.
33
Interestingly,
we found burst neurons in most anterior STN (noM-
STN) in OCD and posterior STN (SM-STN) in PD.
The ratio of burst neurons was equivalent in OCD and
PD and significantly larger (about 35%) than ratios
reported in patients with essential tremor. Both findings
suggest that the anatomically increased distribution of
burst neurons may follow the STN functional organiza-
tion and, therefore, that those neurons may be good
markers of specific deregulation of basal ganglia loops
associated with specific symptoms. At least in PD, this
functional specialization is supported by STN recordings
in patients with PD, which showed that no neuron
located in the ventral segment of the STN exhibited SM
responses, in contrast to the SM-STN located in the dor-
solateral
2
=
3
of the nucleus.
32
In addition, several ana-
tomic and physiologic studies from the monkey suggest
this subdivision with a dorsolateral part of the STN is
involved in the integration of SM inputs and an antero-
ventral part not related to body movement.
33,35–37
Moreover, in OCD, bursts did not exhibit the same
characteristics, possibly because of a lack of dopamine
depletion. According to neurocomputational theories, for
example, synfire chains,
38
bursts are efficient solutions
TABLE 3: Burst Characteristics in OCD and PD
Diag-
nosis
Mean
Duration, s
Number of
Spikes in
Burst
Frequency
in Burst,
Hz
OCD 0.307 6 0.177 12.3 6 4.3 50.9 6 27.8
PD 0.243 6 0.131 14.5 6 5.8 83.4 6 131.2
p 0.01 0.007 <0.0001
Values are means 6 standard deviation.
OCD ¼ obsessive-compulsive disorder; PD ¼ Parkinson
disease.
FIGURE 3: (A) Distribution of the mean frequencies of all
subthalamic nucleus (STN) neurons recorded from patients
with obsessive-compulsive disorder (OCD) and Parkinson
disease (PD). The box plot summarizes the distribution, with
the limits of the box representing the 25th and 75th
quartiles and the central line showing the median sample
value. The whiskers extend to the 95% confidence intervals.
The mean neuronal firing rate recorded in OCD was
significantly lower than that in PD (Mann Whitney U test;
**p < 0.001). (B) The relative proportion of the 2 discharge
patterns among neurons sampled in patients with OCD and
PD. No significant difference was found (chi-square test, p
5 0.76). (C) The relative proportion of the 2 discharge
patterns among neurons recorded within the right and left
STN from OCD and PD. The percentage of burst neurons is
significantly higher in the left side than the right side in
OCD (chi-square test, **p 5 0.03 after Bonferroni
correction), whereas no significant differences were found
in PD (chi-square test, p 5 0.64).
ANNALS of Neurology
6 Volume 000, No. 000
for information encoding. The specific bursts found in
OCD may thus reflect specific pathologic information
processing within the noM-STN basal ganglia loops.
Lateralization of Burst Activity in OCD
Burst neurons were asymmetrically distributed mainly in
the left anterior region of STN in OCD, all right-
handed, whereas the majority of burst neurons in PD
were symmetrically distributed in the dorsal part of the
motor STN (see Fig 4). Conflicting results have emerged
from imaging studies with regard to the distribution and
lateralization of functional abnormalities in OCD. Bilat-
eral dysfunction of the orbitofrontal cortex, the anterior
cingulate, and the head of the caudate nucleus have been
observed using metabolic and functional imaging.
39,40
Other authors have reported a right dysfunction of the
orbitofrontal cortex
41–43
and caudate
40
and have pro-
posed unilateral modulation of the right accumbens nu-
cleus as a therapeutic option.
16
However, left-sided dys-
function has also been underlined in the orbito frontal
cortex,
44
and a volumetric study found decreased gray
matter in the left lateral orbitofrontal, left inferior fron-
tal, and left dorsolateral prefrontal cortex in OCD.
45
A
single lesion in the left ventral caudate can also induce
OCD symptoms,
2
which supports the hypot hesis of an
involvement of the left caudate in OCD.
46
However,
electrophysiologic data recently obtained in the caudate
of 3 patients with OCD failed to demonstrate any
lateralization.
47
This asymmetry may be due mainly to the hetero-
geneity of OCD symptoms that involve several
FIGURE 4: Above, distribution of recorded neuronal
activities with respect to the Morel stereotactic atlas of the
human thalamus and basal ganglia. Filled circles illustrate
burst cells, open circles show irregular cells. Below, 3-
dimensional distribution densities of burst neurons
constructed with normalized coordinates, from all patients,
pooled together and considered as a cloud of points. An
isolated neuron corresponds to a small sphere, and clusters
of neurons are represented as larger blobs. They are
overlaid on a T1 magnetic resonance imaging slice of a
canonical brain in the MNI (Montreal Neurological Institute)
space, at average coordinates of neurons (frontal: z 523.5
mm; horizontal: y 5 12 mm). Parkinson disease and
obsessive-compulsive disorder neuronal activities are
illustrated in blue and red, respectively. Right hemisphere
values are expressed negatively. The midanterior border of
the posterior commissure represents the origins of the
coordinate system. (A) Frontal sections centered on
subthalamic nucleus (STN). Recording sites were plotted
from their normalized coordinates on 3 anteroposterior
overlay sections (gray 5 A 10, dark gray 5 A 12, black 5 A
14). Note that some spots are located outside the boundary
of the STN due to the lack of normalization of the laterality.
(B) Horizontal sections centered on STN. Recording sites
were plotted from their normalized coordinates on 3
overlay dorsoventral sections (black 5 v 4.5, dark gray 5 v
3.6, gray 5 v 2.7). SN 5 substantia nigra; ZI 5 zona incerta;
RN 5 red nucleus; ic 5 internal capsule.
3
Piallat et al: STN Firing in OCD and PD
Month, 2010 7
structures, with relative lateralization.
45
In addition to
pathophysiologic consideration, the asymmetry of dys-
function might have therapeutic consequences.
Medication and Gender as Possible
Confounding Variables
All patients with OCD were receiving serotoninergic
treatment, and 4 were receiving low-dose neuroleptics
(see Table 1). Despite the washout of 12 hours, chronic
pharmacologic treatment of OCD may thus have influ-
enced recorded electrophysiologic activity. Indeed, neuro-
leptic agents have an antidopaminergic effect, which,
according to the rate model of basal ganglia, should indi-
rectly induce an increase of the FR of STN neurons. In
our study, however, because neuroleptic doses were very
low and did not induce any motor side effects, neurolep-
tic agents may have interfered weakly with the activity of
STN neurons.
The same conclusion might be drawn for serotoni-
nergic treatment. It has been shown that acute adminis-
tration of serotonin reuptake inhibitors (SSRIs) activates
STN neurons
48
and that chronic SSRI administration
induces robust inhibition of dopaminergic neurons
49
(which should induce an excitation of STN neurons).
However, this expected increase of FR from serotoniner-
gic medications was not found in our study. The fact
that burst patterns were lateralized on the left side is
another argument against excessive influence from neuro-
leptic and serotoninergic medications on neuronal
activity.
The number of women in the OCD group is sig-
nificantly higher and constitutes a possible confounding
factor. To our knowledge, a single study reported some
gender-related differences in local field potentials
recorded in the STN of patients with PD treated by
L-dopa, showing that the power of the high gamma
band was significantly higher in women.
50
However, it is
difficult to extrapolate these results to single-unit activ-
ities recorded in nonparkinsonian patients.
OCD, STN, and noM Loops of the Basal Ganglia
The dorsolateral part of the STN plays a key role in the
motor loop of the basal ganglia, whereas the ventrome-
dial part is involved in cognitive and emotional loops.
7
In PD, an increase in FR and burst activity in the SM-
STN leads to excessive inhibition of thalamocortical and
brainstem nuclei, resulting in hypoactivation of the pre-
motor and motor cortex. This prevents linkages between
distinct motor programs and could result in akinesia. In
OCD, a disruption in information processing within the
noM loops that connect the prefrontal cortex, the orbito-
frontal cortex, the cingulum, the basal ganglia, and the
thalamus seems to play a central role in compulsive and
obsessive behaviors.
51
Based on our study, we hypothesize
that burst activity reflects a dysfunction in the associative
cortex circuitry mentioned above, preventing the release
of chunks of behaviors,’ which, under normal situations,
create ‘coordinated sequential motor actions and streams
of thought and motivation,’ as already suggested by
Graybiel and Rauch.
52
As a result, this could block the
shifting from 1 concept to another in a patient with
OCD, thus creating a ‘freezing of thoughts.’
Clinical Implications
Despite unknown mechanisms of action, it is now well
established that high-frequency stimulation (HFS)-DBS
of the SM-STN improves motor symptoms in PD. It is
usually accepted that HFS modifies the abnormal STN
discharge pattern and thus restores the neuronal stream
from the basal ganglia output structure to the thalamus.
Here we demonstrate that the noM-STN also has its
own specific burst pattern. We suggest that, first, simi-
larly to the role of the SM-STN in PD, the noM-STN
plays a key role in mediating obsessive-compulsive behav-
ior in OCD. This hypothesis fits well with the significant
proportion of burst neurons found in the noM STN in
OCD. Second, high-frequency DBS-STN would alter
this abnor mal burst pattern, which might explain the
clinical improvements recently reported in OCD.
17,53
To conclude, our electrophysiologic data suggest
that neuronal processing within the noM-STN is dys-
functional in OCD. These results could explain the
potential effect of electrical HFS of the noM-STN to
treat severe OCD.
Acknowledgment
We thank Dr A. Kistner, for help acquiring the clinical
data.
Potential Conflicts of Interest
N.T. has received inscription fees and hotel and travel
expenses for the Neurosurgical Congress from Medtronic.
P.K. has had travel/accommodations expenses reimbursed
by Medtronic. A.L.B. is a board member of University
Hospital Grenoble.
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    • "The mechanisms regulating glutamate spill-over in the SNc may also limit activation of extrasynaptic NMDARs that can couple to cell death signalling pathways and promote excitotoxicity (Hardingham & Bading, 2010; Wyllie et al., 2013 ), particularly under pathological conditions that challenge synapse function; for example, when excitatory drive to dopamine neurons from the subthalamic input is increased or when mitochondria function is compromised, which reduces ATP levels and disrupts the ionic gradients on which glutamate transporters depend. Both of these situations can occur in human patients with PD and in animal models of PD (Magnin et al., 2000; Obeso et al., 2010; Piallat et al., 2011 ). Inhibition of glutamate transporters in SNc induces PD-like signs in rats, in part due to NMDAR-mediated excitotoxicity (Assous et al., 2014). "
    [Show abstract] [Hide abstract] ABSTRACT: NMDA glutamate receptors (NMDARs) contribute to neural development, plasticity and survival, but they are also linked with neurodegeneration. NMDARs at synapses are activated by coincident glutamate release and depolarization. NMDARs distal to synapses can sometimes be recruited by ‘spill-over’ of glutamate during high frequency synaptic stimulation or when glutamate uptake is compromised, and this influences the shape of NMDAR-mediated post-synaptic responses. In substantia nigra dopamine neurons, activation of NMDARs beyond the synapse during different frequencies of presynaptic stimulation has not been explored, even though excitatory afferents from the subthalamic nucleus show a range of firing frequencies, and these frequencies change in human and experimental Parkinson's disease. We report that high frequency stimulation (80 Hz/200ms) evoked NMDAR-EPSCs that were larger and longer lasting than those evoked by single stimuli at low frequency (0.1 Hz). MK-801, which irreversibly blocked NMDAR-EPSCs activated during 0.1 Hz stimulation, left a proportion of NMDAR-EPSC that could be activated by 80 Hz stimulation and which may represent activity of NMDARs distal to synapses. TBOA, which blocks glutamate transporters, significantly increased NMDAR-EPSCs in response to 80 Hz stimulation, particularly when metabotropic glutamate receptors were also blocked, indicating that recruitment of NMDARs distal to synapses is regulated by glutamate transporters and mGluRs. These regulatory mechanisms may be essential in the substantia nigra for restricting glutamate diffusion from synaptic sites and keeping NMDAR-EPSCs in dopamine neurons relatively small and fast. Failure of glutamate transporters may contribute to the declining health of dopamine neurons during pathological conditions.This article is protected by copyright. All rights reserved.
    Article · Sep 2015
    • "These data confirmed that deep brain stimulation applied to this target reduced obsessive–compulsive disorder symptoms (Mallet et al., 2008). Although the reason for this improvement remained unclear, recent electrophysiological data suggest a dysfunctioning of the STN in obsessive–compulsive disorder (Piallat et al., 2011; Welter et al., 2011). Because surgery in these patients makes it possible to record neuronal activity perioperatively in the therapeutic target, we took advantage of this opportunity to test two hypotheses: (i) individual neurons located in the associative-limbic region of the STN might be influenced by cognitive and emotional information; and (ii) doubt revealed by checking behaviour might modify their activity. "
    [Show abstract] [Hide abstract] ABSTRACT: Doubt, and its behavioural correlate, checking, is a normal phenomenon of human cognition that is dramatically exacerbated in obsessive-compulsive disorder. We recently showed that deep brain stimulation in the associative-limbic area of the subthalamic nucleus, a central core of the basal ganglia, improved obsessive-compulsive disorder. To understand the physiological bases of symptoms in such patients, we recorded the activity of individual neurons in the therapeutic target during surgery while subjects performed a cognitive task that gave them the possibility of unrestricted repetitive checking after they had made a choice. We postulated that the activity of neurons in this region could be influenced by doubt and checking behaviour. Among the 63/87 task-related neurons recorded in 10 patients, 60% responded to various combinations of instructions, delay, movement or feedback, thus highlighting their role in the integration of different types of information. In addition, task-related activity directed towards decision-making increased during trials with checking in comparison with those without checking. These results suggest that the associative-limbic subthalamic nucleus plays a role in doubt-related repetitive thoughts. Overall, our results not only provide new insight into the role of the subthalamic nucleus in human cognition but also support the fact that subthalamic nucleus modulation by deep brain stimulation reduced compulsive behaviour in patients with obsessive-compulsive disorder.
    Full-text · Article · Jan 2013
    • "Firing rate was lower in OCD and closer to that of animal controls, and would thus be more " normal " than in PD. On the other hand, burst activity was increased in the anterior ventromedial area, in line with a previous study (Piallat et al., 2011 ) and the associative and limbic functions associated to that area (Karachi et al., 2005 ). Furthermore , a number of burst parameters and oscillatory activities (delta and alpha bands) were correlated to symptom severity; some of these characteristics were predictive of response to treatment by DBS (Welter et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: Since the early 90s, the subthalamic nucleus (STN) has started to be the subject of an increasing interest not only in the community of the basal ganglia scientists but also for neurosurgeons and neurologists, thanks to the development of the surgical treatment for Parkinson's disease. The involvement of the STN in cognitive and motivational processes has been demonstrated since, and psychiatrists are now considering this small structure as a possible target for the treatment of various disorders. In this review, we will address six questions to highlight (1) How increased knowledge has led us from a strictly motor model to an integrative one. (2) How knowledge acquired in animal models can be similar or (3) different from the effects observed in human patients. (4) How clinical trials are sometimes ahead of fundamental research carried out in animals, showing effects that could not be predicted on the basis of animal studies, thus questioning the relevance of some animal models, especially for psychiatric disorders. We will also address the possible future orientations (5) and how the use, or precaution not to use, certain key words in animal research dedicated to STN functions can lead to the omission of a certain amount of available data in the literature (6).
    Full-text · Article · Dec 2011
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