Download Phase-Locked Responses to Pure Tones in the Auditory Thalamus

J Neurophysiol 98: 1941–1952, 2007.
First published August 15, 2007; doi:10.1152/jn.00697.2007.
Phase-Locked Responses to Pure Tones in the Auditory Thalamus
Mark N. Wallace, Lucy A. Anderson, and Alan R. Palmer
Medical Research Council, Institute of Hearing Research, Nottingham, United Kingdom
Submitted 24 June 2007; accepted in final form 11 August 2007
There is considerable divergence and reconvergence of information in the ascending part of the central auditory system
(Cant and Benson 2003; Oliver et al. 1997). In practice, it is
difficult to anatomically identify the cellular components of a
simple ascending pathway between the cochlear nerve and the
cortex (Oliver et al. 1999), but one way of doing so physiologically is by measuring the steady-state delay and upper limit
of phase-locking to pure tones (Liu et al. 2006). In the guinea
pig auditory nerve, action potentials are produced at a particular phase relative to the stimulus waveform (up to a limit of
about 3 kHz) and at a particular delay of 1– 4 ms for cells with
a characteristic frequency (CF) ⬎200 Hz (Palmer and Russell
1986). Thereafter, as activity propagates along a multisynaptic
pathway, the upper limit of phase-locking generally decreases
and the delays increase (de Ribaupierre et al. 1980), even
though the strength of phase-locking can increase as a result of
convergence (Joris et al. 1994). We have previously shown that
phase-locked activity is still present in the primary auditory
cortex of the guinea pig, but by this level the upper limit is 250
Hz and the delays range from 11 to 18 ms (Wallace et al.
2002). If phase-locked information was propagated along parallel, linear pathways between the cochlear nucleus and the
cortex then we would expect to record delays between 4 and 8
ms from the IC and between 8 and 12 ms from the MGB. A
separate way of measuring the delays introduced by conduction
times and synaptic processes is to record click latencies and
these were also measured for most units irrespective of whether
they showed a phase-locked response to tone pips.
In the present study, we measured the delay and upper limit
of phase-locking in the main auditory area within the auditory
thalamus, the medial geniculate body (MGB). Within the MGB
we have recently reported (Anderson et al. 2006) that the
latencies to a brief click vary between the different divisions,
with the shortest latencies in the medial division and the
longest in the dorsal division and shell. As a follow-up we
sought to determine whether there were differences in the
steady-state delays between different thalamic divisions and
whether these correlated with the latencies of the click responses.
In a study of the cat MGB, Rouiller et al. (1979) found
phase-locked responses in only about 2% of thalamic units.
This may have been partly because they assumed that phaselocked responses would be recorded only from units with
sustained responses and these formed about 10% of their
responses. However, in a previous study of the guinea pig
cortex (Wallace et al. 2002), we observed “onset” units that
gave a transient response at CF, but were able to give a
sustained, phase-locked response at 100 Hz. Here we wanted to
determine whether phase-locked responses in the guinea pig
MGB were restricted to sustained units, or whether some cells
with onset properties at CF might show sustained phase-locked
responses at lower frequencies.
Another factor that might affect the numbers of phaselocked responses is the presence of burst firing. Many recent
studies of the thalamus have emphasized the importance of the
tonic versus burst firing modes of the relay cells that carry
information to the cortex. The prevalence of burst firing depends on the state of the animal and in the guinea pig MGB
both sleep states and anesthesia increase the proportion of cells
that show burst firing (Massaux et al. 2004). Thus we wanted
to check whether cells showing burst responses could also
phase-lock.
Pure tones are not a natural stimulus for guinea pigs and so
we also used a conspecific vocalization, termed the purr
(Berryman 1976), that contained a low-frequency fundamental.
We previously showed that a few cortical cells can phase-lock
to the fundamental frequency (270 Hz) of the purr (Wallace
et al. 2002). About 50% of cells in the guinea pig MGB
respond to the purr, although the strength of response is
generally better among cells with low CFs (Syka et al. 1997).
Address for reprint requests and other correspondence: M. Wallace, MRC
Institute of Hearing Research, University Park, Nottingham, NG7 2RD, UK
(E-mail: [email protected]).
The costs of publication of this article were defrayed in part by the payment
of page charges. The article must therefore be hereby marked “advertisement”
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
INTRODUCTION
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0022-3077/07 $8.00 Copyright © 2007 The American Physiological Society
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Wallace MN, Anderson LA, Palmer AR. Phase-locked responses to
pure tones in the auditory thalamus. J Neurophysiol 98: 1941–1952,
2007. First published August 15, 2007; doi:10.1152/jn.00697.2007.
Accurate temporal coding of low-frequency tones by spikes that are
locked to a particular phase of the sine wave (phase-locking), occurs
among certain groups of neurons at various processing levels in the
brain. Phase-locked responses have previously been studied in the
inferior colliculus and neocortex of the guinea pig and we now
describe the responses in the auditory thalamus. Recordings were
made from 241 single units, 32 (13%) of which showed phase-locked
responses. Units with phase-locked responses were mainly (82%)
located in the ventral division of the medial geniculate body (MGB),
and also the medial division (18%), but were not found in the dorsal
or shell divisions. The upper limiting frequency of phase-locking
varied greatly between units (60 –1,100 Hz) and between anatomical
divisions. The upper limit in the ventral division was 520 Hz and in
the medial was 1,100 Hz. The range of steady-state delays calculated
from phase plots also varied: ventral division, 8.6 –14 ms (mean 11.1
ms; SD 1.56); medial division, 7.5–11 ms (mean 9.3 ms; SD 1.5).
Taken together, these measurements are consistent with the medial
division receiving a phase-locked input directly from the brain stem,
without an obligatory relay in the inferior colliculus. Cells in both the
ventral and medial divisions of the MGB showed a response that
phase-locked to the fundamental frequency of a guinea pig purr and
may be involved in analyzing communication calls.
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M. N. WALLACE, L. A. ANDERSON, AND A. R. PALMER
We expected that some thalamic cells would be able to phaselock to the fundamental of the call and possibly even to the first
harmonic.
METHODS
Surgical preparation
Stimulation and recording
Auditory stimuli were delivered to one or both ears through sealed
acoustic systems, consisting of modified Radio Shack 40 –1377 tweeters
joined by a conical section to a damped, 2.5-mm-diameter probe tube
that fitted into the speculum. The system was calibrated in each
experiment by a 2.5-cm-long, 1-mm-diameter probe tube that was
attached to a 0.5-in. microphone (Brüel & Kjær 4134). This
ensured that the same sound levels were consistent across experiments (⫾3 dB). Units were stimulated with 1) tones varying in
frequency and intensity, of 50- or 100-ms duration (cosine-squared
2-ms gated rise/fall time), to establish the frequency response area
(FRA) and CF; 2) low-frequency tones of 200-ms duration (cosinesquared 2-ms gated rise/fall time) to study phase-locked responses;
these were presented at the optimal level for producing good phaselocking in each neuron; and 3) 50-␮s clicks presented at about 60 dB
SPL to study latency and to produce a ringing in the basilar membrane
that causes low-frequency auditory nerve fibers to give a burst of
regular spikes with a period corresponding to their CF (Pfeiffer and
Kim 1972). All these stimuli were presented with a repetition period
of 800 ms. Long-duration stimuli (1 or 5 s, presented at 3- or 10-s
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RESULTS
Identification of MGB divisions using cytochrome
oxidase staining
To reliably locate the position of the phase-locked units we
had to establish the borders of the different parts of the MGB.
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Twenty pigmented guinea pigs of both sexes and weighing 388 –
870 g were used. In 10 animals anesthesia was induced with a single
intraperitoneal (ip) injection of urethane (0.9 g/kg) and surgical
anesthesia was obtained and maintained by giving supplementary
doses of Hypnorm [0.2 ml administered intramuscularly (im), consisting of fentanyl citrate 0.315 mg/ml and fluanisone 10 mg/ml]. The
other 10 animals were anesthetized by an injection of ketamine
hydrochloride [60 mg/kg administered subcutaneously (sc)] followed
by xylazine hydrochloride (Rompun) at 16 mg/kg xylazine (im)
followed by supplementary doses of 15 mg ketamine hydrochloride
(im) as required to achieve surgical anesthesia as judged by abolition
of the forepaw withdrawal reflex. Thereafter urethane was injected
(ip) in doses of 0.1 g in a 20% solution until a stable level of
anesthesia was reached (generally at around 0.9 g/kg). No noticeable
difference was observed in the physiological responses obtained under
the two anesthetic regimes. By using ketamine–xylazine followed by
urethane we had greater control over the final level of anesthesia than
when a single dose of urethane was given initially. Different guinea
pigs had a different susceptibility to anesthetic agents even when they
were from the same breeding colony. A single dose of atropine sulfate
(0.06 mg/kg sc) was given to reduce bronchial secretions.
An incision was made in the external ear flap to provide direct
access to the auditory meatus, which was cleared of wax. All animals
were tracheotomized so that end-tidal carbon dioxide could be monitored and maintained within normal physiological limits by artificially
respiring with oxygen. Core temperature was maintained at 38°C by a
heating blanket and rectal probe. The animals were placed in a stereotaxic
frame, with hollow plastic speculae replacing the ear bars, inside a
sound-attenuating room. A standard stereotaxic position was achieved by
leveling the skull between 5 and 13 mm rostral to ear bar zero, as
described in the atlas of Rapisarda and Bacchelli (1977). A craniotomy
was performed, 5 mm in diameter, usually on the right side alone, so that
electrodes could be inserted vertically into the thalamus. The auditory
thalamus was located at coordinates between 4.7 and 7.1 mm behind
bregma and between 2.8 and 5.3 mm lateral to the midline (see Anderson
et al. 2007). All experiments were performed in accordance with the UK
Animal (Scientific Procedures) Act of 1986.
intervals) were used to establish whether the unit adapted to the
stimulus. Finally, an example of a short guinea pig purr digitized at
44.1 kHz, 1.13-s duration, repeated 30 or 100 times at 3-s intervals, as
used in Wallace et al. (2002, 2005) to test the unit’s ability to
phase-lock to a natural stimulus. The purr was presented at the same
attenuation as that used to obtain the best phase-locked response to a
tone, or at a standard 20-dB attenuation. Recordings from one to three
units at a time were made with glass-insulated tungsten electrodes
(Bullock et al. 1988) advanced by a piezoelectric motor in 2.5-␮m
steps. Electrode tips were 10 –20 ␮m long and typically had impedances of 0.5–2 M⍀ at 1 kHz. Extracellular action potentials were
discriminated using a level-crossing detector (SD1, Tucker-Davis
Technologies), and their time of occurrence was recorded with a resolution of 1 ␮s. In addition, samples of the unit waveforms were captured
and digitized at 100 kHz. Although multiunits were sometimes used to
determine whether phase-locked responses were present, detailed analysis of phase-locked responses was performed only on single units.
The characteristic frequency (CF) was determined either manually
by making a series of peristimulus time histograms (PSTHs) at
different frequencies close to threshold or by automated frequency–
intensity plots based on a randomized presentation of 50-ms tone pips.
One hundred responses to each of a range of frequencies and intensities were used to construct PSTHs. Period histograms were also
plotted and the degree of synchronization (vector strength) was
calculated (Goldberg and Brown 1969; Liu et al. 2006). The vector
strength varies between 0 and 1 and may be artificially high if there
are only a few spikes present. Units were considered to be phaselocked to the stimulus frequency only when their vector strength was
above the 0.1% significance level (Rayleigh test of uniformity ⬎13.8)
(Mardia 1972). The onset portion of the response (0 –30 ms from
stimulus onset) was excluded from the steady-state analysis because it
usually involved a burst of firing that masked the phase-locked
response. The mean best phase angle was plotted against the stimulation frequency (the phase plot) for single units with Rayleigh values
of ⬎100. Units with relatively high Rayleigh values were used to
ensure a reliable value for the mean phase angle. Slopes were
calculated only if there were at least four measurements where the
Rayleigh values were ⬎100. The slopes of these phase plots gave a
measure of neural delay that represents the time between the production of the sound waves and an action potential being recorded in the
thalamus. These values are steady-state delays that should not be
affected by sensitivity to rise time or other problems associated with
estimating onset latency. No correction has been made for conduction
time to the eardrum or the triggering delay for the action potential
because these were constant. The speakers were placed at a constant
distance of 3 cm from the tympanum, the stimuli were all started at the
same phase, and the spikes were filtered at 0.5–3 kHz.
After recording from a track, electrolytic lesions were made to mark
the location of phase-locking cells (5 ␮A for 10 s, electrode negative).
At the end of the experiment, the animal was perfused transcardially
with 0.5 L of 4% paraformaldehyde and 0.5% glutaraldehyde in 0.1 M
phosphate buffer (pH 7.4). The head was then repositioned in the
stereotaxic frame to enable the face of a coronal block to be cut in the
stereotaxic plane. This block was sectioned on a vibratome at 50 or
100 ␮m and sections were stained to demonstrate cytochrome oxidase
activity (Anderson et al. 2007). The electrode tracks and recording
positions of the units were reconstructed in three dimensions using a
microscope with a motorized stage and computer software (Neurolucida, Microbrightfield, Colchester, VT).
PHASE-LOCKING IN THE MGB
Location of units with phase-locked responses
Locations of all units were determined histologically by
making lesions and relating them to the pattern of CYO
staining in coronal sections. Most lesions were used to mark
the beginning and end of tracks through the MGB (dorsal and
ventral lesions in Fig. 1B), but 20 lesions were made at or near
the location where phase-locked cells were recorded. The
lesion in Fig. 1A and the middle lesion in Fig. 1B indicate
phase-locked units at the medial tip of the ventral division.
Four separate units within 300 ␮m of the middle lesion showed
phase-locked responses. All four units had CFs of 0.14 – 0.35
kHz but, despite being located close to each other, they had
different upper limits of phase-locking that ranged from 200 to
480 Hz. The beginning and end of auditory activity were also
marked by lesions in the track shown in Fig. 1C, which is at the
rostral pole of the MGB. Four phase-locked units were recorded between these two lesions. Another pale electrode track
is shown in Fig. 1D and this time the two lesions straddle the
position of three phase-locked cells in the medial division. The
lesions are shown at higher power in Fig. 1F and they clearly
straddle the darkly stained neurons at the center of the medial
division. Another example of a pale track ending in a lesion
marking a phase-locked unit in the medial division is shown in
Fig. 1E and at higher power in Fig. 1G.
The three-dimensional positions of the lesions were reconstructed using Neurolucida software and then they were superimposed on a single reconstruction of the MGB shown in a
planar view from a dorsal perspective (Fig. 2). Each lesion, or
pair of lesions, is shown by a white asterisk; positions of the
lesions shown in Fig. 1, A–E are indicated by the letters A–E
in Fig. 2. The lesions occur in three clusters: one at the caudal
pole of the medial division (D and E), one along the medial
edge of the ventral division (A and B), and a single pair at
the rostral pole of the ventral division (C). These results
show that in the ventral division the phase-locked cells are
restricted to a discrete band of cells with low (⬍1.4 kHz)
FIG. 1. Coronal sections of the thalamus stained for cytochrome oxidase activity. Ventral (V) division is outlined by the dashed white line; the solid white
line marks the border of the medial (m) division. Lesions are marked by black arrows with a white border and electrode tracks by small white arrows. A: lesion
at the edge of the medial tip of the ventral division, close to the caudal pole of the medial geniculate body (MGB). Characteristic frequency (CF) of a phase-locked
unit here was 180 Hz. B: total of 3 lesions have been made in 2 nearby tracks at locations where there was auditory driving. Dorsal lesion is in the suprageniculate
nucleus (SG), the ventral is in the shell division (S), and the middle lesion is again at the medial tip of the ventral MGB. Four phase-locked units were located
at the medial tip of the ventral division, close to the middle lesion. This section is at a more rostral part of the MGB than A and contains the caudal part of the
lateral geniculate nucleus (LGN) immediately above the dorsolateral zone (DL) of the MGB. C: section at the rostral pole of the MGB showing 2 lesions at the
edges of the ventral MGB. Pale line marked by arrows indicates the electrode track and 4 phase-locked units were recorded from this part of the track. All had
CFs of between 250 and 500 Hz. D: section about 400 ␮m from the caudal pole of the MGB showing a pale electrode track passing through the SG. Toward
the end of this track there are 2 lesions in the medial division that straddled 3 phase-locked units with CFs of 800 –1,270 Hz. E: section about 600 ␮m from the
caudal pole of the MGB showing a pale electrode track and a single lesion in the medial division. The lesion was close to a phase-locked unit with a CF of 600
Hz. At this level the relatively high enzyme activity of the anterior pretectal nucleus (APT) can be seen. F: higher-power view of section shown in D.
G: higher-power view of section shown in E. Scale bars in A–E are 1 mm and in F and G are 250 ␮m.
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The four main divisions of the MGB were identified by
staining coronal sections for cytochrome oxidase (CYO) and
using criteria we have defined previously (Anderson et al.
2007). The ventral division (V) of the MGB has relatively high
CYO activity and forms an ovoid structure in the middle of the
MGB (outlined by dashed white line in Fig. 1). The precision
with which it is possible to define the border of the ventral
division varies depending on its adjacent structures: the border
with the medial division is defined by pale fiber bundles and
can be determined to within 0.1 mm whereas the border with
the dorsal division involves a more gradual change in the
enzyme levels and is more difficult to discern. The medial
division (outlined by the solid white line in Fig. 1) mainly has
diffuse borders and contains a cluster of densely stained neurons at the caudal and middle levels of the MGB. The cells are
shown at a higher magnification in Fig. 1, F and G, interspersed among pale-staining fiber bundles. Dorsal to the ventral and medial divisions lies the less densely stained dorsal
division, which is subdivided into a dorsolateral (DL) and more
medial suprageniculate (SG) zones (Fig. 1, B and D). At the
caudal, ventral, and lateral margins of the ventral division there
is a band of paler staining corresponding to the shell (S)
division of the MGB (Fig. 1, A and B). At the caudal portion of
the MGB the dorsal division is bounded by the lateral posterior
nucleus (LP) as shown in Fig. 1E.
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M. N. WALLACE, L. A. ANDERSON, AND A. R. PALMER
CFs that are tightly arranged along the medial and rostral
edges.
Of the 275 units recorded from the MGB, most (53%) were in
the ventral division, with 22% in the medial division, 16% in the
dorsal division, and 9% in the shell division (see Table 1). A total
of 18% of units were phase-locked, but these were not evenly
distributed between divisions: 40/146 (27%) of ventral units
and 9/60 (15%) of medial units showed phase-locked responses. No phase-locked activity was recorded from the
dorsal and shell divisions despite the fact that some of the units
in these divisions had CFs of ⬍1 kHz. The sample of units
recorded was not random because we oversampled the lowfrequency parts of the MGB where phase-locked responses
were more common. Because most of the phase-locked units
(98%) were recorded from parts of the MGB where the CFs
were ⬍1.4 kHz we could not obtain an accurate value for the
total percentage of phase-locked units in the MGB. In our data
43% (40/94) of low-frequency (⬍1.4 kHz) units in the ventral
division showed phase-locked (P-L) responses (Table 1). In the
medial division, 28% (8/29) of the low-frequency units showed
phase-locked responses and 3% (1/31) of high-frequency units.
TABLE
FIG. 3. Peristimulus time histograms (PSTHs) showing a variety of response types recorded from single neurons in the MGB in response to CF
tones, 50 ms in duration, presented at 20 dB above threshold. Classification and
CF of each unit are indicated at the top right of each panel and the duration of
the stimulus is indicated by the horizontal bar.
Types of units that phase-locked
Recordings were made from 241 single units and 34 multiunits within the MGB that responded to pure tones. For all
units, PSTHs were measured in response to tones 20 dB above
threshold at their characteristic frequency (CF). Different
workers tend to classify temporal responses in slightly different
ways. We used the same criteria as those used by Edeline et al.
(1999) except that we subdivided the sustained units into three
groups (Fig. 3, right column). Out of all the units, 51%
(140/275) showed a transient type of response that included
onset, offset, or on-off responses (see examples in Fig. 3). The
distinction between offset and late responses was established
by varying the duration of the stimulus. True offset units
showed a consistent latency after the end of the stimulus. Some
of the onset units (including the one illustrated) showed a
regular firing pattern involving two or more spikes at consistent
1. Range of CFs and click latencies in the four divisions of the MGB
Ventral
Total number of units
Range of CFs, kHz
Number of P-L units
Range of phase delays, ms
Mean and SD of phase delay
Range of click latencies in P-L units, ms
Mean and SD of click latencies
Number of non–P-L units
Range of click latencies in non–P-L units, ms
Mean and SD of click latencies
Medial
⬍1.4 kHz
⬎1.3 kHz
⬍1.4 kHz
⬎1.3 kHz
94
0.07–1.3
40
8.6–14
11.14, 1.6
7–12.8
9.02, 1.6
54
6.3–18.5
9.74, 2.3
52
1.4–10.4
0
29
0.18–1.3
8
7.5–11
9.26, 1.5
3.1–9.3
5, 1.9
21
4.3–15.1
8.67, 3.2
31
1.5–20
1
52
6.5–18.5
9.2, 2.2
P-L, phase-locking.
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Dorsal
Shell
45
0.1–24.5
0
24
0.3–18.6
0
45
7.7–32.3
13.1, 5.1
24
9.3–40.9
24, 10.8
3.8
30
4.1–15.5
8.14, 2.95
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FIG. 2. Planar view of a 3-dimensional reconstruction of the medial and
ventral divisions of the right MGB based on cytochrome oxidase–stained
coronal sections. Positions of lesions marking the location of phase-locked
units in the MGB are shown by the large white asterisks. White letters A–E
mark the lesions that are illustrated in Fig. 1, A–E. L, lateral; R, rostral.
PHASE-LOCKING IN THE MGB
FIG. 4. Bar charts showing the proportion of units with 6 different types of
temporal response recorded in the ventral and medial divisions of the MGB.
Non-phase-locked (non-PL) units are shown by the black bars and the phaselocked (PL) units by the white bars. Onset group includes onset-choppers and
the on-sustained group includes on-sustained-off units.
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did not. Only two of the six units (on-sustained and pauser)
showed a phase-locked response at CF. Many of the highfrequency units were tested at CF only because they did not
give a significant response at 100 Hz (as indicated by the
frequency response area), which was the other main frequency
used in searching for phase-locking. Only one unit with a CF
of ⬎1.3 kHz was identified as showing evidence of phaselocking; this was a broadly tuned unit in the medial division
that also responded at 100 Hz.
Some cells clearly responded at 100 –300 Hz but gave no
evidence of a phase-locked response. This may result from the
lack of an effective phase-locked input from the inferior
colliculus (IC), but could also be the result of intrinsic membrane properties. We could not study the membrane dynamics
directly but were able to look at the pattern of action
potential generation. Some of the phase-locked units
showed bursts of two to four spikes separated by 2- to 4-ms
intervals in their spontaneous activity (Fig. 5, C–F). Bursts
of spikes were also often observed during the onset response
(Fig. 5, A and B) of phase-locked units, but these units
showed tonic firing during the sustained part of the phaselocked response (Fig. 5, G–I). Thus some of the phaselocked units were able to switch from burst firing to tonic
firing as they became entrained to the stimulus frequency.
Burst firing was common among MGB units, especially
when they were stimulated at CF, but some bursting units
did not show evidence of bursting activity when stimulated
at low frequencies.
Monaural versus binaural responses to tones and clicks
The responses to binaural tones and a click are illustrated in
Figs. 6 and 7, which show the same, representative phaselocked unit in the ventral MGB. When stimulated with a tone
of 140 Hz the onset response is followed by a sustained
phase-locked response that continues for the duration of the
200-ms stimulus. Weaker phase-locking is still observed at 180
Hz but, by 220 Hz, while there is still some sustained activity
after the onset response, it is not locked to the stimulus phase.
Similarly at CF (450 Hz) there is a little sustained activity, but
it is not phase-locked. In this particular unit, there is a late
response occurring at about 140 ms after the stimulus onset
whether it is a tone or a click. The main response to the click
is a prominent onset response.
The unit in Fig. 6 was phase-locked at frequencies from 60
to 180 Hz and showed its strongest phase-locked responses to
an 80-Hz binaural stimulus (Fig. 7A). The stimulus frequency
giving the strongest phase-locking response was chosen to
compare the monaural responses with the binaural. For this
unit stimulating the left (contralateral) ear produced an onset
response that was as strong as the binaural response but there
was much less sustained activity and it was not phase-locked
(Fig. 7C). Stimulating the right ear produced a small onset
response and some sustained activity that was weakly phaselocked to the stimulus (Fig. 7E). Thus the phase-locked component of the response showed binaural facilitation where the
binaural response was much greater than the sum of the
monaural responses.
All units were stimulated with binaural tones because this
was the most reliable stimulus but 17 of the best phase-locking
units were also stimulated monaurally to assess the relative
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intervals (chopping). For all onset units the firing rate was at or
below the background rate by the end of the 50-ms stimulus.
The remaining units (49%, 135/275) had a sustained response where the firing rate was still above background at the
end of the stimulus. Most of these cells had a sharp onset and
continued to fire at a lower rate throughout the duration of the
stimulus (on-sustained units). There were two other types of
sustained unit: buildup responses where there was no onset
response, but a gradual increase in firing rate during most or all
of the stimulus, and pauser responses where the firing rate fell
to background after the onset response before rising again. The
temporal response pattern of some units was observed to
change with frequency: some units with a transient response at
CF showed a sustained response at frequencies around 100 –
200 Hz (where phase-locking was most likely to occur). Out of
the 275 units recorded, 49 (18%) showed evidence of phaselocking to at least one stimulus frequency (Fig. 4). Of these
phase-locked units, 25 (51%) had transient responses at their
CF, whereas 24 had sustained responses at their CF. Thus units
that showed a transient response at their CF were as likely to
show phase-locking to low frequencies as units with sustained
responses at CF.
The number of units that phase-lock to pure tones may have
been underestimated. All units were stimulated at CF, but
many of the high-frequency units were not stimulated at the
low frequencies where phase-locking was found to occur.
Indeed only 13/49 units that showed phase-locked responses
did so at their CF, and none of these had a CF of ⬎800 Hz.
Three of the units illustrated in Fig. 3 showed a phase-locked
response at 100 Hz: only the offset, on-off, and buildup units
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M. N. WALLACE, L. A. ANDERSON, AND A. R. PALMER
Variation of phase-locking strength with stimulus frequency
and duration
FIG. 5. Examples of the waveform (A) and a raster plot (B) of a unit in the
medial MGB that showed a burst response with 2 or 3 spikes at the onset of a
tone at its CF (610 Hz). Examples of waveforms and raster plots of burst firing
recorded in the spontaneous activity of 2 phase-locked units from the ventral
(C, E) and medial (D, F) divisions of the MGB. In the raster plots groups of
2, 3, or 4 spikes are indicated by the small arrows. Example of a raster plot (H)
and PSTH (I) from a single unit in the ventral MGB. Response is phase-locked
to a stimulus of 220 Hz, 78 dB SPL, and 200-ms duration. Waveform of the
stimulus is shown in G.
contribution of each ear individually. Out of these 17 units, 8
showed a clear dominance for the contralateral (left) ear with
the ipsilateral ear either not producing any response by itself (3
units) or producing an onset response with only weak evidence
of phase-locking (vector strength ⬍0.2). Five of the units
showed a clear preference for the ipsilateral ear, with the
contralateral ear not producing any strong (vector strength
⬎0.2) phase-locking. All the ipsilaterally dominant units were
located in the ventral MGB. Three of the units gave a strong
(vector strength ⬎0.2) phase-locked response only to a binaural stimulus, and either did not respond or gave only weak
phase-locking to either ear alone. Only one unit showed good
phase-locking to stimuli presented to each ear individually and
binaurally.
J Neurophysiol • VOL
The effective range of frequencies that could produce
significant phase-locked responses in the ventral MGB
ranged between 60 and 520 Hz, whereas in the medial
division it was 60 –1,100 Hz. The vector strengths for
individual units varied over this range in either a low-pass or
a band-pass fashion. Examples of these two types of response are shown in Fig. 8 by plotting vector strength
against stimulus frequency.
Units were classified as band-pass if their vector strength
increased by ⬎20% from the lowest frequency at which they
gave a robust response to a frequency that was ⱖ40 Hz higher.
Among the single units in the ventral division, 10 were classified as low-pass and 15 as band-pass. Within the medial
division, five single units were classified as low-pass and two
as band-pass. Other units did not give phase-locked responses
over a wide enough range of frequencies to classify them. The
peaks of the band-pass units varied in frequency between 100
and 300 Hz. In a study of phase-locking in the cat MGB most
responses were low-pass, but band-pass responses were also
described (Rouiller et al. 1979).
We mainly used tones of 200-ms duration in this study, but
in some units responses to tones of 1 or 5 s were recorded. Six
units in the ventral division and three in the medial division
were stimulated for 1 s. Two of the ventral units were also
stimulated for 5 s. All continued to show phase-locked responses throughout the period of stimulation. For all units there
was a dip in firing rate after the onset response but, after the
first 200 ms, the firing rate and vector strength remained fairly
constant for the remainder of the stimulus. Only two of the
units [one from the ventral division (CF 220 Hz) and one from
the medial division (CF 610 Hz)] had vector strengths ⬎0.9;
these values were found only at frequencies of 100 and 150 Hz
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Most units were also stimulated binaurally with a click; this
was an effective stimulus for nearly all the units and it allowed
us to measure the response latency to one stimulus at a constant
sound level. The response for the unit shown in Fig. 6 was
typical in that it had a brief onset response that lasted about 20
ms. This onset was composed of five peaks of increased firing
probability that were spaced about 1.5 ms apart (Fig. 7B). A
similar regular response occurred when the left ear was stimulated (Fig. 7D) but the response to the right ear, although
multipeaked, had peaks that were less regular and more widely
spaced (Fig. 7F). A regular firing pattern was observed in the
click responses of all eight medial MGB units that gave
phase-locked responses to tones, and in 18/26 phase-locked
units in the ventral MGB. We wanted to determine whether this
regular firing might be directly related to the ringing of the
basilar membrane and the regularity of the afferent input
(Pfeiffer and Kim 1972) or to a regular chopping activity
linked to the membrane properties of the thalamic cell. Consequently the period between the multiple peaks of the click
response was converted to a frequency value and this was
plotted against the CF of the unit at 60 dB SPL (the sound level
of the click). There was only a weak correlation (R2 ⫽ 0.003)
between the click response frequency and the CF. Among the
units, as the CF varied, there was no consistent change in the
frequency of the regular response to click.
PHASE-LOCKING IN THE MGB
1947
FIG. 6. Examples of the responses from a typical single unit recorded in the ventral MGB, during stimulation with a range of frequencies or a 50-␮s click
presented to both ears. Frequency of the stimulus is indicated in the top right of each panel and the duration by the horizontal bar. Unit phase-locks at 140 Hz
but not at the other frequencies shown.
Upper limits and delays of phase-locked responses
to pure tones
The upper limit of significantly phase-locked responses varied
between units and between divisions as shown in Fig. 9A. The
upper limits in the ventral division varied between 80 and 520
Hz, whereas in the medial division they varied between 100
and 1,100 Hz. These upper limits were significantly different
(using Scheffé ANOVA, P ⫽ 0.001). We also measured the
steady-state delays of single units in both structures. The mean
phase angle varied linearly with the stimulation frequency as
shown by the phase plots in Fig. 9B. The slope of these plots
FIG. 7. Same unit as shown in Fig. 6. PSTHs of the response to an 80-Hz
tone presented at 79 dB SPL for 200 ms to both ears (A), the left ear (C), and
the right ear (E) and PSTHs of the responses to a 50-␮s click on an expanded
timescale in the right column. Click was presented to both ears (B), the left ear
(D), and the right ear (F). Vector strength of phase-locking (r) and the Rayleigh
value are shown for each panel in the left column. Vector strengths were based
on period histograms of the sustained response to the 80-Hz tone from 30 to
200 ms after stimulus onset.
J Neurophysiol • VOL
corresponds to the steady-state delay. When the steady-state
delays were plotted against the upper phase-locked limit, (Fig.
9C) there was a trend (R2 ⫽ 0.43) for shortest delays to be
found with the highest upper limits. We have previously
collected similar data for cortical area AI (Wallace et al. 2002)
and the IC (Liu et al. 2006) and these are plotted for comparison in Fig. 9D.
The units in the MGB and IC show almost the same range of
upper limits for phase-locking, but the range of MGB delays is
narrower. Not surprisingly some units in the IC have delays
that are ⱕ4 ms shorter than any in the MGB, but a few units in
the rim of the IC (dorsal cortex and external nucleus) also have
delays that are ⱕ6 ms longer than any in the thalamus. There
is also some overlap between MGB and AI units, with a few
thalamic units having lower upper limits and longer latencies
FIG. 8. Examples of single, phase-locked units showing the variation of
their synchronization (vector strength) with the stimulus frequency (log scale).
Units shown by solid or dashed lines are from the ventral division; units shown
with a dotted line are from the medial division. A: band-pass units. B: low-pass
units.
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(Fig. 8). The strongest phase-locking was always found at
frequencies below CF for units in the medial division and for
most units in the ventral division. Only 3/30 units in the ventral
division had their highest vector strength at CF (CFs of
100 –250 Hz) and one unit had its highest vector strength at a
frequency above CF (CF was 180 Hz).
1948
M. N. WALLACE, L. A. ANDERSON, AND A. R. PALMER
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FIG. 9. A: plot of upper limit of phase-locking to pure tones against the CF of units in the ventral and medial divisions of MGB. Four of the medial units
(open triangle) have limits higher than those of any in the ventral division (solid circle). B: phase plots derived by plotting the mean phase angle against the
stimulus frequency for single units from the medial and ventral divisions. Slope of these lines corresponds to the steady-state delays of these units as indicated
at the bottom right. C: plotting the upper limit of phase-locking against the steady-state delay derived from phase plots from both divisions of the MGB showed
that there was a correlation between these 2 parameters. A linear regression line had an R2 ⫽ 0.43. D: a similar correlation between the upper limit of
phase-locking and the steady-state delay was also seen for units recorded previously in the central nucleus of the IC (ICC), primary auditory cortex (AI), and
the dorsal cortex and external nucleus of the IC (ICCx) and these are plotted together with the results from MGB. E: plot of click latencies vs. steady-state delay
for phase-locked units in the medial and ventral divisions. Dotted line indicates where the points would lie if both values were the same. F: plot of click latency
vs. CF for the non-phase-locked units in the ventral and medial divisions of the MGB. Units in both divisions have a wide range of CFs and the shortest latencies
are found in the medial division at all frequencies.
J Neurophysiol • VOL
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PHASE-LOCKING IN THE MGB
1949
Phase-locking to the fundamental frequency of a vocalization
A short guinea pig purr was used to stimulate 30 of the MGB
units that showed phase-locked responses to tones. We used
the same example of purr as had previously been used in
studying the cortex (Wallace et al. 2005). This example contains nine rhythmic pulses of sound as shown by its waveform
in Fig. 10A. Nearly all (27/30) of the units tested gave a
response to multiple pulses of the purr call. An example of a
response from a unit in the medial division is shown in Fig.
10B and the mean response to the purr in the 21 phase-locked
units recorded from the ventral MGB is shown in Fig. 10C.
Most of the units responded to all of the pulses of sound, with
the largest response usually to the first pulse and the smallest
responses to pulses 2, 3, and 9, which were the least intense
pulses. Pulses 6, 7, and 8 were the most intense and produced
the most consistent responses. The waveform of pulse 6 is
shown for a 50-ms-long segment of the call in Fig. 10D;
Fourier analysis of this segment in Fig. 10E shows that it has
a fundamental frequency at 267 Hz, and harmonics at 534, 801,
and 1,068 Hz. Pulse 6 produced the most consistent response
across units in both divisions of the MGB and responses to this
pulse have been analyzed in detail in the cortex (Wallace et al.
2002).
Units phase-locking to tones of 300 to 600 Hz should also
phase-lock to the fundamental and possibly the first harmonic
frequency of the purr. To test this, we performed an autocorrelation on the PSTH of the purr response between 515 and 565
ms after stimulus onset.
An example of a response from a ventral MGB unit that
phase-locked to tones of ⱕ480 Hz is shown in Fig. 10F. The
response shows eight peaks of activity at regular intervals and
the autocorrelogram (Fig. 10G) shows three prominent peaks at
3.75, 7.55, and 11.45 ms. The major peak is at a lag time of
3.75 ms, corresponding to a frequency of 267 Hz. The other
J Neurophysiol • VOL
FIG. 10. A: waveform of the example of short purr used in this study. There
are 9 main pulses of sound, each of which is numbered. B: example of the
response to purr from a single unit in the medial division of the MGB. Cell
responds to each of the 9 pulses. C: PSTH of the mean response to the short
purr taken from the responses of 21 phase-locked units from the ventral
division of the MGB. D: waveform of pulse 6 shown on an expanded timescale
(50 ms long). E: fast Fourier transform (FFT) of pulse 6 showing the peaks of
a harmonic series starting at 267 Hz. F: PSTH of response to 100 repetitions
of pulse 6 by a single ventral MGB unit that phase-locked to pure tones of
ⱕ480 Hz. G: autocorrelogram of response shown in F showing the number of
correlated spikes for time lags between 1 and 25 ms. Prominent peaks occur at
3.75, 7.5, and 11.45 ms and these correspond to the indicated frequencies.
peaks correspond to 133 and 87 Hz and represent spikes
occurring locked to the purr but not on adjacent cycles. Of the
11 units in the ventral MGB that phase-locked at ⱖ250 Hz and
were stimulated with the purr, eight gave responses with
autocorrelation peaks corresponding to 260 –267 Hz. The other
three gave strong responses where the spikes were not locked
to any of the stimulus frequencies and there was no sign of
regular firing within the response to a single pulse. None of the
units gave a prominent peak in the autocorrelogram corre-
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than the best units in AI. Altogether, there is much more
overlap in the latencies and upper limits than would be expected for a simple linear hierarchy.
In some units different pathways may mediate the onset and
the tonic phase-locked response. If the same pathways were
involved in both responses the two parameters should covary.
However, when click latency was plotted against steady-state
delay (Fig. 9E), there was no correlation (R2 ⫽ 0.06) between the
two parameters (for the 26 units where these measurements were
available).
The ranges of steady-state (phase) delays are 4 – 6 ms for
both the ventral and medial divisions (Table 1) and their means
are significantly different (t-test, P ⫽ 0.016). The ranges of
click latencies for the cells that phase-lock to tones in both the
ventral and medial divisions are about 6 ms and their means are
significantly different (t-test, P ⫽ 0.003). In the medial division the mean of the click latencies for the cells that phase-lock
is also significantly different from those that do not phase-lock
(t-test, P ⫽ 0.001). The range of click latencies observed
among the non-phase-locked cells of the ventral and medial
divisions are shown in Fig. 9F. The shortest click latencies are
clearly in the medial division over a wide range of frequencies.
The shorter latencies and delays in the phase-locked cells of the
medial division than those among any other group in the MGB
(Table 1) imply they have a unique afferent input.
1950
M. N. WALLACE, L. A. ANDERSON, AND A. R. PALMER
a phase-locked response in the MGB of the anesthetized cat
(Rouiller et al. 1979) may be a significant under representation
at least for high-level stimuli. A much higher proportion of
phase-locked cells was found in the awake restrained rabbit
(15.6%) (Stanford et al. 1992). However, although the electrode tracks were widely distributed and apparently randomly
positioned, only cells sensitive to interaural time differences
were tested (mainly low-frequency cells), and so this study
may also have overestimated the number of phase-locked cells
in the MGB. Because there is no evidence of phase-locked
responses in the dorsal or shell divisions, the proportion of
phase-locked responses in the ventral division must be higher
than that for the MGB as a whole. Among the low-frequency
cells (CF ⱕ1.3 kHz) of the ventral division the proportion of
cells showing phase-locking may be ⬎40% in the guinea pig.
DISCUSSION
Sources of phase-locked input to the MGB
Types and numbers of phase-locked cells in the MGB
Spike timing is an important way of coding spectral information at the level of the cochlear nucleus (Lavine 1971) and
the lower brain stem (Oertel 1999), but by the level of the
neocortex temporal mechanisms are thought to have largely
been replaced by rate or place mechanisms (Phillips et al.
1991). One factor in this change could be burst firing in cells
of the MGB. In the rat auditory thalamus there is in vitro
evidence that burst firing induces a slow after-hyperpolarization (AHP) that can inhibit neuronal firing over many seconds
(Hu and Mooney 2005). If this slow AHP were present in vivo
it would prevent bursting cells from showing a sustained,
phase-locked response. This mechanism did not appear to be
operating in our anesthetized guinea pigs because many of the
cells with phase-locked responses also showed evidence of
bursting in their onset response and during spontaneous activity (using the criteria for bursts of Massaux et al. 2004).
According to the different burst criteria of He and Hu (2002)
some cells recorded from both medial and ventral divisions
were bursting during the sustained, phase-locked activity.
The current study provides further evidence that for lowfrequency (⬍1 kHz) stimuli, temporal mechanisms may still
have a role in spectral analysis. Indeed, there may be a higher
proportion of phase-locked cells in the MGB than was previously thought (Rouiller et al. 1979). Uncertainty about the
proportion of MGB units that can give a phase-locked response
to a tone remains; an accurate assessment of the proportion
would require random sampling and an unanesthetized preparation to avoid the effects of anesthetics. Anesthetics may
reduce the accuracy with which central neurons can fire action
potentials: in a study of IC cells in the awake rabbit, Kuwada
et al. (1989) showed that the addition of barbiturate anesthesia
reduced the sensitivity to interaural time differences.
None of the studies of phase-locked responses in the MGB
(cat: Rouiller et al. 1979; rabbit: Stanford et al. 1992) used
random sampling methods. In the cat study, only 10% of
high-frequency units (those with a sustained response) were
stimulated with the low frequencies to which a phase-locked
response was most likely to occur. Other neurons were stimulated at CF. We have shown that many cells that have an onset
response at CF can give a sustained, phase-locked response at
low frequencies. Thus the estimate of 2–3% of cells that gave
J Neurophysiol • VOL
The main source of phase-locked input to the MGB is the
inferior colliculus (IC). The central nucleus of the IC provides
the main ascending input to the ventral division of the MGB
(Malmierca et al. 1997; Wenstrup 2005; Winer 1992). Although the current study is consistent with the IC providing a
phase-locked input to the ventral division only a small proportion of this input will be producing phase-locked excitation.
Somewhere between 10 and 30% of fibers from the IC are
inhibitory (Peruzzi et al. 1997; Winer et al. 1996) and will not
contribute to phase-locking directly. Among the low-frequency
cells in the IC 68% showed some evidence of phase-locking
(Liu et al. 2006), although it is not known how many of these
provide excitatory input to the ventral MGB. None of the units
in the ventral MGB phase-locked at ⲏ520 Hz, whereas cells in
the IC phase-locked at ⱕ1,000 Hz (Liu et al. 2006). The
presence of synaptic jitter and longer membrane time constants
could account for the reduction in the upper phase-locking
limit in going from the IC to the ventral MGB (de Ribaupierre
et al. 1980). Vector strengths as high as 0.96 were found in
one cell of the ventral MGB, but vector strengths of ⱕ0.99
have been observed in the guinea pig IC (Liu et al. 2006) and
the presence of convergent inputs may actually increase vector
strengths of output cells (Joris et al. 1994). Overall, the presence of such high vector strengths in the ventral MGB is
consistent with an input from the central nucleus of the IC. The
other major source of afferent input to the MGB is the auditory
cortex (Winer 1992, 2005), but there is no evidence to suggest
that the cortex provides any significant phase-locked input to
the MGB in any species. Similarly there is no evidence that the
external nucleus or dorsal cortex of the IC provides a phaselocked input.
The presence of binaural facilitation and the weak or nonexistent phase-locking produced by monaural stimulation, in
many cells, is consistent with some form of coincidence
detectors of the type shown in the superior olive (Goldberg and
Brown 1969). The complexity of the inputs was further illustrated by the lack of binaural facilitation in either the onset
response or the click response observed in most units. The
click response was usually multipeaked and in a few cases
the interval between the peaks coincided with the period of the
cell’s CF. Thus for a few cells the click response may have
represented the ringing in the basilar membrane that causes the
firing in cochlear nerve fibers to be locked to their CF (Pfieffer
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sponding to the first harmonic frequency of 534 Hz. In three of
the units the responses to pulses 5–9 also gave autocorrelation
peaks at 260 –267 Hz.
In the medial MGB, four of the units phase-locked to tones
of ⱖ600 Hz and two showed phase-locking at ⱕ400 Hz. All
six of these units gave multiple peaked responses to the purr
and showed autocorrelation peaks corresponding to frequencies of 260 to 274 Hz in response to pulse 6. However, none
was phase-locked to the first harmonic of 534 Hz. Non-phaselocked cells also responded to all nine pulses of the purr but
with no sign of regular firing within the response to a single
pulse.
Overall, we found that most (16/20, 80%) units that phaselocked to 250-Hz tones also phase-locked to the fundamental
frequency of the purr.
PHASE-LOCKING IN THE MGB
TABLE
1951
2. Steady-state delay and upper phase-locking limit in six auditory structures
Delay
Number of units
Range of delays, ms
Mean delay ⫾ SD
Upper limit of phaselocking
Number of units
Range of upper limits, Hz
Mean upper limit ⫾ SD
Central IC
Medial MGB
Ventral MGB
Cortical Belt (VRB)
Cortical AI
Rim of IC
57
4.6–15.4
8.2 ⫾ 2.8
7
7.5–11
9.3 ⫾ 1.5
19
8.6–14
11.1 ⫾ 1.6
3
10.5–14.6
12.5 ⫾ 2.1
18
11.1–18.3
14.9 ⫾ 2.4
11
12.1–21.3
15.4 ⫾ 3.1
95
115–1,034
444 ⫾ 250
8
150–1,100
569 ⫾ 349
40
60–520
231 ⫾ 119
12
70–300
116 ⫾ 73
46
100–400
175 ⫾ 79
13
70–330
167 ⫾ 91
Functional role of phase-locked responses
Cells in both the ventral and medial divisions of MGB in the
cat were shown to phase-lock to frequencies of ⬎1 kHz
(Rouiller et al. 1979) and it has been suggested that these cells
are important in analyzing the low-frequency components of
vocalizations (de Ribaupierre 1997). Our results are consistent
with that proposal; some cells in both divisions were able to
code the fundamental frequency of the purr. Both the short purr
J Neurophysiol • VOL
and the longer-lasting, but otherwise similar, long purr are
important communication calls in the guinea pig (Berryman
1976). The short purr (alarm rumble) is used as a mild alarm
signal, whereas the long purr (rut rumble) is used during
courtship behavior (Arvola 1974; Rood 1972). The detailed
temporal analysis of these calls may have a role in identifying
individuals or in mate selection. The fundamental frequency of
the purr is expected to become lower with increasing age and
lengthening of the vocal tract and this could provide one way
for distinguishing between young and adult animals. Cells in
cortical AI of the guinea pig also code temporal information on
the fundamental frequency of these calls (Wallace et al. 2002).
In conclusion, this study has shown that phase-locking is
exhibited by a significant number of cells in the MGB and that
the frequencies involved are ethologically important for the
guinea pig. Evaluating the quality and latency of these phaselocked cells also provides useful information about the input
pathways to individual cells and indicates that even nearby
cells may have radically different input pathways.
ACKNOWLEDGMENTS
We thank Professor J. Syka for providing digitized recordings of a guinea
pig purr and Dr. T. M. Shackleton for help with analyzing our results.
Present address of L. A. Anderson: UCL Centre of Auditory Research, 332
Gray’s Inn Road, London, WC1X 8EE, UK.
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