Download Visual and Oculomotor Functions of Monkey Subthalamic Nucleus

JOURNALOF NEUROPHYSIOLOGY
Vol. 67, No. 6, June 1992. Printed
in U.S.A.
Visual and Oculomotor Functions of Monkey Subthalamic Nucleus
MASARU
MATSUMURA,
JUN KOJIMA,
THOMAS
W. GARDINER,
AND OKIHIDE
HIKOSAKA
Laboratory of Neural Control, National Institute for Physiological Sciences, Okazaki, 444, and Department
of Neurosurgery, Gunma University School of Medicine, Maebashi, 371, Japan
SUMMARY
AND
CONCLUSION
1. Single-unit recordingswere obtained from the subthalamic
nuclei of three monkeystrained to perform a seriesof visuooculomotor tasks.The monkeysweretrained to fixate on a spotof light
on the screen(fixation task). When the spot wasturned off and a
target spot came on, they were required to fixate on the target
quickly by making a saccade.Visually guidedsaccades
were elicited when the target cameon without a time gap(saccadetask).
Memory-guided saccadeswere elicited by delivering a brief cue
stimuluswhile the monkey wasfixating; after a delay, the fixation
spotwasturned off and the monkey madea saccadeto the rememberedtarget (delayed saccadetask).
2. Of 265 neuronstested, 95 showedspike activity that was
relatedto someaspectsof the visuooculomotor tasks,whereas66
neuronsrespondedto active or passivelimb or body movements.
The task-relatedactivities wereclassifiedinto the following categories: eyefixation-related, saccade-related,visual stimulus-related,
target- and reward-related,and lever release-related.
3. Activity relatedto eye fixation ( YI= 22) consistedof a sustained spikedischargethat occurredwhile the animal wasfixating
on a target light during the tasks.The activity increasedafter the
animal startedfixating on the target and abruptly ceasedwhenthe
target went off. The activity wasunrelated to eyeposition. It was
not elicited during eye fixation outsidethe tasks.The activity decreasedwhen the target spot wasremoved.
4. Activity related to saccades(~1= 22) consistedof a phasic
increasein spikefrequency that wastime locked with a saccade
madeduring the tasks.The greatestincreasesoccurred predominantly after saccadeonset.This activity usually wasunrelatedto
spontaneous
saccades
madeoutsidethe task. The changesin activity typically were optimal in one direction, generally toward the
contralateralside.
5. Visual responses
(~2= 14) consistedof a phasicexcitation in
responseto a visual probe stimulusor target. Responselatencies
usuallywere 70-120 ms. The receptive fieldsgenerallywere centeredin the contralateralhemifield, sometimesextending into the
ipsilateralfield. The receptive fieldsincluded the fovea1region in
sevenneurons;most of theseneuronsrespondedbestto parafoveal stimulation. Peripheralstimuli sometimessuppressed
the activity of visually responsiveneurons.
6. Activity related to target and reward ( YI= 29) consistedof
sustainedspike dischargethat occurred only when the monkey
could expect a reward by detectingthe dimming of the light spot
that he was fixating. This activity was present regardlessof
whetherthe monkey obtainedthe rewardby releasinga lever or by
just maintaining fixation on the target. Eye fixation on a light
stimulusmay not beprerequisite:sometimesit startedevenbefore
the target point cameon.
7. Among neuronsexhibiting activity that wasrelatedto lever
releaseduring the task ( YI= 49)) four different types of responses
were recorded: excitation before lever release,excitation after
lever release,inhibition before lever release,and a combination of
excitation and inhibition. Theseneurons showedno changein
activity in relation to limb movementsmadeoutsidethe tasks.
8. Neuronsrelatedto visuooculomotortaskswerelocated primarily in the ventral part of the subthalamicnucleus,whereas
neuronsresponsiveto skeletomotormovementswere found predominantly in the dorsalpart.
9. Theseresultsare consideredin relation to the current view
that the subthalamicnucleussendsexcitatory signalsto the substantia nigra parsreticulata, which in turn exertstonic inhibition
of saccadicburst cellsin the superiorcolliculus. In contrastto the
caudate-nigralconnection, which would play a role in the initiation of saccades
by a disinhibitory mechanism,the subthalamic
nucleusmight act to suppresseye movements.The suppressive
mechanismwould act to maintain eye position on an object of
interest,prevent unwantedeyemovementsunder specificcircumstances,or recover eyefixation once a saccadeis executed.
INTRODUCTION
The subthalamic nucleus (STN) is in a crucial position to
influence the output of the basal ganglia. It projects to the
internal and external segments of the globus pallidus (Carpenter et al. 198 1a; Groenewegen and Berendse 1990; Kita
and Kitai 1987; Nauta and Cole 1978; Parent and Smith
1987; Smith et al. 1990) and the substantia nigra pars reticulata (SNr, Canteras et al. 1990; Carpenter et al. 1968,
198 lb; Kanazawa et al. 1976; Kita and Kitai 1987; Nauta
and Cole 1978; Parent and Smith 1987; Smith et al. 1990),
the major output structures of the basal ganglia system. It
also projects to the pedunculopontine
nucleus (Nauta and
Cole 1978; Parent and Smith 1987; Smith et al. 1990). Inputs to STN are multiple. Signals arising from the caudate
and putamen are conveyed to STN via the external segment
of the globus pallidus (Kim et al. 1976; Kita et al. 1983;
Moriizumi et al. 1987; Percheron et al. 1984). The cerebral
cortex is another source of input. STN receives direct projections from several frontal cortical areas ( Afsharpour 1985;
Hartmann-von
Monakow et al. 1978; Kiinzle 1977, 1978;
Kiinzle and Akert 1977; Petras 1969).
Motor functions of STN have been suggested by both
clinical and physiological studies. A lesion localized to STN
produces hemiballismus
(Carpenter 198 1). This has been
confirmed experimentally by making lesions in STN in the
monkey (Carpenter et al. 1950; Crossman et al. 1984;
Whittier and Mettler 1949). Abnormal neural activity in
STN may underlie different types of movement disorders
(Crossman 1987; Mitchell et al. 1985a,b, 1989). Cells are
found in STN that change discharge rates during skeletal
movements and in response to somatosensory stimulation
(DeLong et al. 1985; Georgopoulos et al. 1983).
In addition to skeletomotor functions, the basal ganglia
are thought to be involved in both oculomotor and cogni-
0022-3077192 $2.00 Copyright 0 1992 The American Physiological Society
1615
MATSUMURA
1616
tive functions (Hikosaka and Wurtz 1989; Wurtz and Hikosaka 1986 ) . Oculomotor functions are controlled in part
by the caudate-nigro-collicular
pathway. SNr exerts a tonic
y-aminobutyric
acid (GABA)ergic inhibition on the superior colliculus (Hikosaka and Wurtz 1983d, 1985). During
saccadic eye movements, this inhibition appears to be suppressed transiently by GABAergic inhibition
originating
from the caudate nucleus (Hikosaka et al. 1989a-c) . Such a
disinhibition
occurs when the animal attempts to make a
saccade volitionally to a visual or remembered target. Presaccadic activity has been shown to occur in caudate neurons and is believed to suppress the tonic spike discharge of
SNr neurons, leading to a disinhibition
of output neurons
in the superior colliculus (Hikosaka et al. 1989a). In addition, cells that are related to eye fixation, visual, auditory,
cognitive, and reward-related functions are found in the
caudate nucleus as well as in SNr (Hikosaka and Wurtz
1983a-c; Hikosaka et al. 1989b,c).
Although the responses of STN neurons have been studied during limb movements, their activity has not been studied in relation to visuooculomotor
functions. Possible oculomotor functions for STN are suggested by its afferent connections from the cortical eye fields (Huerta and Kaas
1990; Huerta et al. 1986; Stanton et al. 1988) and its efferent connections to SNr (Nauta and Cole 1978; Parent and
Smith 1987; Smith et al. 1990). Because STN appears to
play an important role in motor control, and damage to
STN has been implicated in many movement disorders, its
potential role in oculomotor functions is important to establish. Therefore in the present study we have investigated
the activities of STN neurons in relation to visuooculomotor behavior in alert monkeys. We have found that nearly
20% of the STN neurons examined were indeed related to
visuomotor functions. The majority of these neurons were
found in the ventral part of STN. A preliminary report of
this work appeared elsewhere in abstract form (Matsumura
et al. 1991a,b).
METHODS
We studiedsingle-cellactivities in STN of three alert monkeys
(Macaca fuscata, adult male, Je-8.4 kg, Er-1 1.O kg, Iv-9.0 kg)
while they were performing visuooculomotor tasks.In one monkey, both hemispheres
were surveyed.In the other two monkeys,
only the left sidewassurveyed.The monkeysweretrained to perform a seriesof behavioral paradigms(seebelow). The monkeys
were kept in separateprimate cagesin an air-conditioned room.
At each experimental session,usually twice a week, they were
brought to the experiment room. The monkeys were given restricted fluid during periods of training and recording. Their
healthconditions,suchasbody weightand appetite,werechecked
daily. Supplementarywater and fruit wereprovided daily.
Surgical procedures
The monkeysweresedatedwith ketamine(4.6-6.0 mg/ kg) and
xylazine ( 1.8-2.4 mg/ kg) given intramuscularly,and then general
anesthesiawasinduced by intravenousinjection of pentobarbital
sodium (4.5-6.0 mg kg-’ h-l). Surgical procedureswere conducted under asepticconditions in an operating room. After the
skull wasexposed,holesfor lo- 15acrylic screwsweredrilled in it.
The screwswere bolted into the holes and fixed with a dental
acrylic resin.The screwsactedasanchorsby which a headholder
l
l
ET AL.
and a chamber,both madeof delrin, werefixed to the skull. Useof
metal in the headpiecewasavoidedto permit magneticresonance
imaging( seebelow). The chambersweretilted 40” laterally in the
coronal planeand aimedat the center of STN [ 15mm anterior, 6
mm lateral, and 2 mm in height, basedon the atlasof M. fuscata
(Kusama and Mabuchi, 1970)].
An eyecoil wasimplanted over oneeyefor measurementof eye
position with the use of a method modified from Judge et al.
( 1980). The eyecoil consistedof Teflon-insulatedmultistranded
stainlesssteel wire (Cooner Sales,0.3 mm OD) that was preformed into a 16-to l&mm diam coil with three completeturns.
The coil wasleft in a pouch madeunder the conjunctiva -5 mm
posterior to the lateral limbal margin. The twisted lead wasthen
threadedthrough a hole madeon the lateral wall of the orbit. The
twisted lead wasthreadedthrough a silicon tube (5 mm OD) to
allow the eyeto rotate freely. The silicon tube with the leadinside
wascoveredwith a dentalacrylic resinandfixed to a smallconnector mounted on the skull. The animalsreceivedantibiotics (sodium ampicillin, 23-30 mg/kg im eachday) after the operation.
Behavioral
tasks
The monkey satin a primate chair in a dimly-lit and sound-attenuatedroom. The monkey’sheadwasfixed, and in front of him
wasa tangent screen(57 cm from his face) onto which smallred
spotsof light werebackprojected.The fixation point and the target
point wereback-projectedspotsof light from light-emitting diodes
(Toshiba, TLRA 150-C) and had a diameter of 0.2”. The projection systemconsistedof an LED light source,a pinhole aperture,
and a projector lens.Three LED projectorswereused:the first one
wasfor the fixation point, and its light wasprojecteddirectly onto
the screen.The secondand the third oneswerefor the target point
and another irrelevant stimulus,and their lightswerereflectedvia
two galvanomirrorsthat controlled the horizontal and vertical positionsof the light spots.
The basictask of the monkey wasto fixate hisgazeon a spotof
light until it becamedim. If the spotsteppedfrom one location to
another, the monkey was required to move his line of sight by
making a saccadiceye movementto refixate the spot.
To differentiatethe characteristicsof STN neurons,we usedtwo
setsof paradigms.The first set required both eye fixation and
manipulationof a lever (lever tasks); the secondsetrequired only
eye fixation (eye tasks). Each setincluded different types of eye
movementtasks.
LEVER TASKS. Figure 1 illustratesthe paradigmsincluded in this
category.Although different typesof eyemovementswereelicited,
theseparadigmsall required manipulation of a lever. When the
monkey depresseda lever on the chair, a spot of light (fixation
point) cameon at the center of the screen.After a random period
of time, the spotdimmed. If the monkey releasedthe lever within
a shortperiod of time (0.5-0.7 s) after the dimming of the light, he
wasrewardedwith a drop of water. If he releasedthe lever earlier
or later, the trial terminatedwith neither reward nor punishment.
The trial alsoterminated without reward when eye position deviated from the fixation point by more than a prefixed value
(usually 3” in a horizontal or vertical direction) during the fixation period (except for the first 0.7 s,which wasallowedfor gazeto
settledown). Successivetrials were separatedby an inter-trial interval of l-3 s (randomized).
In the fixation task, the central fixation point (F) becamedim
after 1.5-3.5 s with no other visual stimulusbeingpresented.In
the fixation task with stimulus,a secondspotof light (S) appeared
briefly (50 ms) during the fixation period ( 1.5-3.5 s). The monkey wasrequiredto maintain fixation without makinga saccadeto
the stimulus.This task wasusedto study the visual responses
of
STN neurons.The saccadetask was designedto evoke visually
guidedsaccades.
The fixation point wasturned off after a random
VISUOOCULOMOTOR
FIXATION
TASK
FIXATION
TASK
WITH
STIMULUS
FSACCADE
TASK
DELAYED
3
SACCADE
T
TASK
/
ACTIVITY
IN SUBTHALAMUS
1617
EXPERIMENTAL
PROCEDURE. In most ofthe experiments,the
location of the target point wasselectedfrom 32 points (8 directions with 5, 10, 20, and 30” eccentricity, Fig. 1, bottom). When
spike activity of a singleneuron was isolated,we performed an
initial screeningprocedure to test whether the neuron had any
visuooculomotor properties. This consistedof the saccadetask
and the delayedsaccadetask, both requiring the useof the lever;
the targetpoint waschosenrandomly out of four directions(right,
left, up, and down) with the eccentricity of 20”. If task-related
activities were observed,we ran a seriesof experiment in blocks
usingdifferent taskswhile recordingthe unitary spikeactivity and
eyemovements.For eachblock of experiments(usually consisting
of 40 trials), target pointswereusedthat hadthe sameeccentricity
but different directions (8 or 4 directions). The target location
alsocould be moved manually. This permitted usto determinethe
visual receptive fieldsand movement fieldsof neurons.
Recording procedures
To determinethe location of STN, we obtainedmagneticresonanceimagesof the brain beforeunit recording(Hitachi Laboratory MRIS, 2.11 tesla). The magneticresonanceimagesprovided
the approximatelocation of the STN in relation to the XYZ coordinate of the chamber. Glass-insulatedElgiloy microelectrodes
(Suzuki andAzuma 1976, lo- 15MQ measuredat 10Hz, exposed
tips 15-20 pm) were usedfor extracellular recordingof singlecell
activities in STN. The electrodesweredriven by a hydraulic X- Y
coordinate micromanipulator (MO-95, Narishige, Tokyo) that
was attached to the chamber. In one hemisphere,we surveyed
FIG. 1.
Top: behavioral paradigms. F: fixation point (a central spot of STN widely to study the topography of the responses
within STN.
light that the monkey must fixate to start a trial). E: schematic eye posiIn other hemispheres,
we implanted guidetubes(Teflon tube, 1.2
tion. S: stimulation point [a spot of light that was used to detect visual
mm OD) one at a time for repeatedelectrodepenetration. Inserresponse (fixation task with stimulus)]. T: target point [a peripheral spot
tion
of the guide tube wasperformedunder anesthesiawith ketathat monkey must fixate after the central fixation point went off (saccade
task)]. In the delayed saccade task, this spot was also turned on briefly as mine hydrochloride. Eye movementswere recordedwith the use
the cue of a future target while the monkey was fixating. The depression at of the magneticsearch-coiltechnique ( Robinson 1963) .
The behavioraltasksaswell asstorageand display of data were
the end of the filled area represents dimming of the spot. Bottom : locations
of the fixation point and target points (o ) . In most experiments, the target controlled by computer (PC 9801 RA2 1, NEC, Tokyo). Eyeposipoint was chosen from 32 points at 5, 10,20, and 30° from the center in 8 tions were digitized at 500 Hz and stored continuously during
directions. The directions of the targets are represented by the numbers of each block of trials. The unitary action potentials were passed
filled dots. In the raster displays of the following figures, filled dots are used through a window discriminator, and the times of their occurto indicate the direction of target in each trial.
renceswere storedwith a resolution of 1 ms.At the time of each
experiment, spike rastersand eye position data were displayed
period of time ( 1S-2.5 s), and another spot of light [target point on-line on the computer monitor.
(T)] cameon at the sametime. The target point dimmed after a
The monkey’sbehavior wascontinuously monitored by an inrandom period of time (0.5-2.0 s). The monkey madea saccade frared camera. The camerasystem,with the use of mirrors, alto the target point and releasedthe lever in responseto its dim- lowed us to observebody movementsof the monkey in two perming. The delayed saccadetask wasdesignedto evoke memory- spectives:first, to seegrossmovements(hand/arm movements
guided saccades.While the monkey was fixating, another light associatedwith manipulation of the lever, postural changes,and
spot(cue stimulus)cameon briefly (50 ms), which indicated the foot /leg movements)and second,to seemovementsin the face
location of a future target point. The monkey was required to (eye movements,eyeblinks, and oral movementsassociatedwith
maintain fixation for 2-3 s, until the fixation point went off. The water intake). To examine somatosensoryand skeletomotorremonkey then wasrequiredto initiate a saccadeto the remembered sponses,
body partsof the monkey weremanipulatedby the experlocation of the cue stimulusbeforean actualtarget point cameon, imenter. Eachmonkey wasconditioned to relax during thesema600 mslater. When the target cameon, the monkey then fixated nipulations. Spike discharge during these manipulations was
on the target to detect its dimming and obtain reward.
monitored with the oscilloscopeand audiomonitor. The responses
EYE TASKS. The samesetof eyemovement taskswereincluded wereevaluatedby at leasttwo observers.
in this category,which, however,did not require manipulation of
a lever. The monkey wasrewardedwhen he maintained fixation Histology
on a target spotuntil it becamedim. Appropriate fixation of gaze
Severalmarking lesionswereplacedby passingpositive currents
within the eyeposition window wasrequired (seeabove); the size
of this window wasmadelarger for more eccentrictargets.When (2 PA for 200 s) through the recording electrodes.The marks
eyepositionwasmaintainedwithin the fixation window, a reward madefor eachpenetration usually wereplacedat similar depths,
wasgiven 300 ms after the dimming; failure to maintain fixation 2-3 mm aboveSTN. This produceda distinct pattern in the histoterminatedthe trial. When the task waschangedfrom a lever task logical sections.A few marks were alsomade at the siteswhere
to an eye task, the monkey ceasedto usehis hand during several STN neuronswere recorded(Figs. 2 and 3).
trials. Thus eye taskshelpedto differentiate visuooculomotor reAt the end of the experiments, each monkey was perfused
sponses
from limb movement-related responses.
transcardially with saline followed by 4% paraformaldehyde,
1618
MATSUMURA
ET AL.
plotted alongthe identified tracks;their depthswerecalculatedby
the distancesto the depth of the marks that were read on the
electrodemanipulator at the time of experiment. Here we took
into account the extent of tissueshrinkagedue to fixation, which
wasestimatedto be 10%on the basisof the distancesbetweenthe
marks.
The location of the guide tube wasobvious in the histological
sections.The depths of the recording siteswere determined by
comparing the manipulator readoutsof the electrodesand the
identified marking lesions.
RESULTS
FIG. 2. Photomicrograph of a histologtcal section showing the left STN
of monkey Je, stained with cresyl violet. Arrow: an iron deposit made by
passing positive currents through the recording electrode, showing the position where a saccade-related neuron was recorded. Calibration bar: 1
mm.
under deeppentobarbital sodiumanesthesia.The headthen was
fixed to the stereotaxicdevice,and the brain wascut in the coronal
planeinto blocksof 12 mm thickness.The brain waspostfixed for
2 wk. Serialcoronal sections(40 pm) werecut on a cryotome and
stainedwith cresylviolet.
Reconstruction qf electrode penetrations
The marking lesionswere visualizedon histologicalsectionsas
round iron deposits.On the sidewithout any guidetube for electrodes,among33 penetrations,all but two of the electrodetracks
could be identified. The recordingsitesof STN neuronsthus were
A total of 265 neurons were recorded from STN in four
hemispheres of three monkeys, their locations later being
confirmed histologically. As shown in Table 1, 95 neurons
responded during the task; 66 neurons responded during
the animal’s active movements or in response to passive
manipulation
of the body. No responses were observed in
the remaining 104 neurons.
General characteristics of STN neurons
Background discharge rate of neurons in STN ranged
from 5 to 48 spikes/s (mean 18.47, SD 8.8 >and presented a
unimodal distribution. Unit discharge patterns were usually
irregular, sometimes occurring in doublets or triplets. No
significant differences were found in background discharge
rate between responsive cells and unresponsive cells. Visual
responses were frequently found adjacent to STN in the
zona incerta, where unit discharges usually were regular
and tonic. As expected, visuomotor-related
activity was
also commonly found in SNr.
Classification of task-related activities
Neurons related to the behavioral tasks were further classified as fixation-related,
saccade-related, visual-, targetand reward-related, and lever release-related. Note from
Table 1 that individual neurons sometimes exhibited more
than one type of activity. However, the neurons that preTABLE
1.
ClussiJicationof activities qfsubthalamic neurons
Types of Activities
Task-related responses
Saccade
Visual
Fixation
Target and reward
Lever-release
Skeletomotor responses
Orofacial
Neck and trunk
Soulder
Arm and hand
Leg
Nonspecific
Unresponsive
All Tested
FIG. 3. Location of the left STN and the surrounding structures at the
same level shown in Fig. 2. This corresponds to the rostrocaudal level,
A14.5, as illustrated in Fig. 4. CP, cerebral peduncle: GPi, internal segment
of the globus pallidus: IC, internal capsule: OT, optic tract: STN, subthalamic nucleus: SNc, substantia nigra pars compacta: SNr, substantia nigra
pars reticulata: ZI, zona incerta.
Number of Units
22
14
22
29
49
21
16
8
12
4
5
104
265
Many neurons showed more than one type of response and thus are
included in more than one category. Thus the number of responses exceeds
the number of neurons tested. Skeletomotor responses included both activities related to the animal’s active movements and those related to passive
movements.
VLSUOOCULOMOTOR
ACTIVITY
IN SUBT ‘HALAMUS
1619
FIG. 4.
Locations
of neurons with visuooculomotor
activities
( l ) and neurons with skeletomotor
activities
(o ) that were recorded from the left STN of monkey
Je.
Bars: locations
of neurons
that showed no response.
They are plotted along the reconstructed
electrode penetrations obtained from the coronal histological
sections.
The sections are arranged
in caudaI-to-rostra1
sequence
[ from A 13.5 to A 16.0, on the basis of the atlas of the
brain of M. jimala
(Kusama
and Mabuchi
1970 )] , each
separated
by OS mm. The identified
electrode
tracks
were projected on the nearest section. Symbols along the
electrode tracks indicate the types of response: F, fixation; S, saccade; V, visual; T, target and reward. Neurons
with 2 types of activity are indicated by conjugated
symbols (e.g.. S, V). Calibration
bar: 1 mm.
sented activity related to visuomotor
usually not accompanied by skeletomotor
behaviour
activity.
were
Topogru ph I1~
Figure 4 illustrates the locations of visuooculomotor
neurons and other (skeletomotor
responsive) neurons recorded in one hemisphere. The majority of visuooculomotor-related neurons were located in the ventral part of STN,
and they tended to form clusters. No obvious segregation
was found between visuooculomotor
neurons that exhibited different types of responses during testing. In contrast,
skeletomotor neurons tended to be located in the dorsal
part of the nucleus. Although we found no evidence of a
clear somatotopic organization in our sample, there was
some tendency for orofacial responses to be found in the
dorsolateral part of STN, trunk-related responses in the
dorsal area, and limb-related responses in its central area.
These responses were recorded from neurons that were in-
120
0
120 0
I I 11OOms
7LO7NOl,Ol/SAC
5. A left STN neuron with activity related to eye fixation ( lever task; saccade task). This neuron discharged tonically
while the monkey was fixating on either the fixation
point (F) or the target point (T). 7’011 to hottrm:durations
of fixation
point ( F) and of target point (T), horizontal
eye positions [ H ( up: rightward,
down: leftward )] , vertical eye positions [ V up:
upward, down: downward],
spike frequency
histogram,
and raster display of spike discharges. The records are aligned with
respect to of&s
of saccadcs made to the fixation point ( /P$), fixation point offset ( WIW),
and target point offset (I?~@).
Because the durations
of these events were different across trials, the records are shown as interrupted.
Each line in the raster
display represents the activity
of the neuron during a single trial, each dot indicating
a single spike discharge. The target
points were located at 20” from the fixation point in 4 directions.
Their directions
are indicated by the dots at the left of the
raster line ( see Fig. 1 ). The raster lines were reordered
with respect to the direction
of the target point, though direction
was
selected randomly
at the time of the experiment.
Calibration
for the histogram
indicates a discharge rate of 40 imp/s,
calibration
for eye traces 20°, and time scale represents
100 ms. All subsequent
figures use these conventions
unless
otherwise stated.
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FIG. 6. Effects of fovea1 light stimulation
on neural activity related to eye fixation. When the fixation point was turned off
briefly (600 ms) while the monkey
was fixating center panel, spike activity of this STN neuron decreased transiently
(lever
task; fixation task). Figures are aligned with respect to onset (lcrfi), blink-off
(~~~ntcr), and offset ( rQ#) of the fixation point.
vo
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CONTRA
IPSI
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A left STN neuron that discharged during
saccades to both visual targets [ /~JJ)(eye task; saccade
task)] and remembered
targets [ httr1n7
(eye task;
delayed saccade task)].
Trials were realigned
and
grouped
into contralateral
(CONTRA
) and ipsilatera1 ( IPSI ) ones. each with 3 directions
( horizontal.
oblique up, and oblique down ). Contralateral
saccades. but not ipsilateral
saccades. were accompanied by increases in spike activity. Spike activity was
greater
for memory-guided
saccades than for visually guided saccades (Y < 0.00 1. Mann-Whitney
C’
test ). All the figures are aligned with respect to saccade onset. The eccentricity
of the targets was W.
H------/bt= ‘2oo
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VISUOOCULOMOTOR
ACTIVITY
MEMORY-GUIDED
VISUALLY-GUIDED
-
-
1621
SACCADES
SACCADES
-E
-400
IN SUBTHALAMUS
-
0
FIG. 8. Time course of saccade-related activities in
STN neurons. The start and end of each line indicates
the onset and offset respectively, of saccade-related activity for each neuron in relation to saccade onset. No statistical difference was observed between the times of the
onsets or offsets of the neuronal responses during visually guided saccades(saccade task) vs. memory-guided
saccades (delayed saccade task). Saccade-related activity
usually occurred after the saccade onset.
-
4OOmsec
I
-400
I
I
I
0
I
termingled and appeared in clusters over the whole rostrocaudal extent of the nucleus.
Visuooculomotor
activities
Twenty-twoneurons
exhibited sustained spike activity during attentive fixation,
either on the fixation point or target point. However, these
changes in firing rate were not observed during spontaneous fixation outside the task. Examples of such responses
are presented in Figs. 5 and 6. In most cases (Fig. 5), discharge rate increased gradually after the fixation point
came on and the monkey made a saccade to it. This fixation-related activity was sometimes preceded by an anticipatory discharge. The activity could be interrupted if the
ACTIVITYRELATEDTOEYEFIXATION.
I
I
I
400msec
visual target was removed from the central visual field. This
was typically observed during the saccade task, when the
fixation point was replaced with a peripheral target point
(Fig. 5 ) ; 14 of 2 1 tested neurons showed a transient decrease of firing, and this occurred during the period when
the monkey made a saccade to the peripheral target. The
activity also ceased abruptly when the target went off at the
termination of the trial. A similar transient decrease of firing was observed when the fixation point was blinked off for
a short period while the monkey was fixating (Fig. 6). The
latencies of the off responses ranged from 107 to 174 ms
(mean 130.8 ms, SD 19.6 ms). In the seven other neurons,
decreases in firing rate at the time of fixation off were unclear.
‘8
‘0/- /-- ‘,88
FIG. 9. Direction selectivity of saccade-related activity. For each neuron, response indexes for 8 directions of saccades
(eccentricity: 20 deg) are shown as a polar plot. Solid and hatched lines: response indexes for visually guided and memoryguided saccades, respectively. The polar plots are shown only for those neurons in which sufficient data were obtained for all
of the 8 directions. The index was defined by the equation T/C; C and T: mean discharge rates within a control period and a
test period, respectively. The control period was a 1,OOO-msperiod starting 1,000 ms before offset of the fixation point; the
test period was set by eye to cover the total period of the responsive phase of saccadic activity. Hatched circle: response index
of 1, indicating no change in spike activity; points outside and inside the circle indicate increase and decrease of spike
activity, respectively. The side ipsilateral to the neuron is shown on the left and the contralateral side on the right.
16’3--
MATSUMURA
ET AL.
The fixation-related
activity was unrelated to the position of the fixation target. As illustrated in Fig. 5, discharge
rates were virtually the same whether the monkey was fixating at the central fixation point ( F) or one of the four peripheral target points (T) 20° eccentric to the center. None of
the neurons recorded in STN showed significant relation to
the position of the eye during fixation.
Fixation-related
neurons
usually exhibited
irregular
changes in spike frequency during fixation. There was no
indication, however, that the changes were related to the
accuracy of fixation or to small fluctuations of eye position.
RELATED
TO SACCADES.
Twenty-two
neurons exhibited saccade-related spike activity. This activity was associated with saccades made to either visual or remembered
targets during the task; it appeared not to be related to spontaneous saccades made outside the task. Among 18 neurons
fullvd tested, saccade-related activity was greater for mem-
ACTIVITY
ory-guided saccades than for visually guided saccades for
seven neurons, as shown in Fig. 7. In four neurons, it was
greater for visually guided saccades; the responses of the
other seven neurons were equally related to both types of
saccades.
The onsets of saccade-related neural activity usually ( 1 I/
16 visually guided; 12/ 17 memory guided) preceded the
onsets of the saccades (Fig. 8). This activity outlasted the
saccades, however, usually by 100-400 ms, and the greatest
changes in activity occurred predominantly
after saccade
onset.
Saccade-related neurons had optimal saccade directions.
In Fig. 9 the polar plot of saccadic response indexes for each
neuron is shown. The majority of the cells exhibited greater
responses during contralateral saccades. A decrease of activity was sometimes observed with ipsilateral saccades (e.g.,
neurons 2, 3, and 9).
Ten of 22 saccade-related neurons also exhibited visual
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FIG. 10.
Combination
of visual and
saccade-related
activities.
G/J: in the saccade task (lever task), this right STN neuron showed a burst of spike activity in response to the onset of the target point to
which the monkey
made a saccade. The
location of target point was 3” from center
( imct ). The h istogram
and raster arc
aligned with respect to the onsot of the target point. U~NWK in the delayed saccade
task (eye task ), the neuron exhibited
both
a visual response ( first burst) and a saccade-related
response ( second burst). The
sum of these responses,
however.
was
smaller than the activity
seen during the
saccadc task. The histogram and raster are
aligned with respect to the onset of the target cue ( /L$) and onset of saccade ( righf ).
111m11,
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VISUOOCULOMOTOR
ACTIVITY
1623
IN SUBTHALAMUS
A
IPSI
n=14
---
30
n=t4
20
Latencies
of visual
msec
responses
FIG. 1 f . Visual receptive
fields (A ) and latencies of visual responses (B) of STN neurons. In A, the numbers along the
abscissa indicate degrees from the central fixation point. Circular areas: field in which visual stimuli evoked responses from
each neuron.
responses. The neuron in Fig. 10, for example, showed a
burst of spikes before a small upward saccade to a visual
target (top). The delayed saccade task (bottom) indicated
that this was a combination
of visual and saccadic responses. The combined presaccadic activity (top) was
greater than the sum of the individual responses (bottom).
Such enhancement
rons.
Vis ml rc3pomc~~s
Fourteen neurons responded to visual stimuli presented
while the monkey was actively fixating the central fixation
E20 /
/
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+ ‘5D32N07.12/SACD
was seen in three of nine tested neu-
E30/,$,,
-1
’
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/
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5D32N07
:*/SACD
FIG. 12.
Visual response of a left STN neuron. LX/~,: while the monkey
was fixating, a spot of light presented at 3” to the
right produced a phasic visual response ( lever task; delayed saccade task ). Figures are aligned on the onset of target cue. The
duration
of the visual stimulus was 50 ms. Right: polar plots of visual response indexes for eccentricities
ranging from 3 (E3)
to 30 deg (E30).
Response index was calculated
for each of 8 stimulus directions.
The index was defined as the ratio of the
mean discharge rate within a test period to the mean discharge rate within a control period (see Fig. 9 ). The control period
was a 500-ms period before stimulus onset; the test period was from 80 to 180 msafter stimulus onset, which was set by eye to
cover the total period of the excitatory
visual response. The increase in spike frequency
was limited to a small region in the
upper right quadrant
near the center. Spike activity was suppressed by more peripheral
stimuli; this suppression
was nearly
complete for stimuli IO0 (see HO) from the center.
1624
MATSUMURA
point. As presented in Fig. 1 1 A, the receptive fields of these
neurons were centered predominantly
contralaterally to the
side of the recording site. These receptive fields sometimes
extended into the ipsilateral side as well. The receptive field
had a gradient, with the response magnitude reducing gradually as the location of the stimulus was shifted away from
the center of the receptive field. Seven out of 14 neurons
had receptive fields that included the central fovea1 region;
these neurons typically were more responsive to parafoveal
stimuli. The latencies of visual responses ranged from 70 to
118 ms (mean 98.0, SD 18.1, Fig. 11 B).
In nine neurons, firing rate decreased when a visual stimulus was presented outside its excitatory receptive field, either on the side contralateral to the excitatory receptive
field (n = 6) or in the region surrounding the excitatory
receptive field (n = 3). An example of the latter type
(surround inhibition type) is shown in Fig. 12. This neuron
increased its activity in response to contralateral perifoveal
stimuli (I[$), but its activity was strongly suppressed by
more peripheral stimuli in all directions (see ElO). This
suppression was even greater for stimuli presented in the
same direction as the excitatory receptive field (see E30).
In two cells, the activity evoked by a visual stimulus persisted until the monkey made a saccade to the remembered
location of the visual stimulus (Fig. 13). This sustained
activity was direction selective, corresponding to the receptive field of the initial visual response; no significant activity
was evoked for stimuli that elicited memory-guided
saccades in other directions.
ilT
I
ET AL.
RELATEDTOTARGETANDREWARD.
Twenty-nine
neurons presented activity that was related to the monkey’s
fixation on the target point, which was followed by the delivery of reward; these neurons were not activated while the
animal was fixating on stimuli that were not directly associated with reward. We have categorized this type of response separately from fixation-related activity (described
above) because of its clear dependence on reward.
Examples of these responses are shown in Figs. 14 and
15. The neurons became active only when the monkey began to fixate on a target spot that was expected to dim. The
activity was present irrespective of the location of this fixation point.
When the task was changed such that the central spot
became dim (Figure 14, hottom), after several trials the
neuron became active while the monkey was fixating on it.
The same result was obtained in all of the four neurons
tested. This further indicates that the reward expectancy
attached to the spot of light was critical for these neuronal
responses.
The reward-related activity was observed even when the
eye tasks were performed without manipulating
the lever
(unlike the neuron shown in Fig. 17), suggesting that these
neurons were not concerned with actual type of movement
employed for obtaining reward. We monitored the monkey’s behavior during this period with the use of an infrared
camera (see METHODS)
but found no evidence of consistent
body movements, including postural changes, licking movements, and other orofacial movements; rather, the monkey
usually withheld gross movements.
ACTIVITY
I
H
V
FIG. 13.
this activity
remembered
absent when
raster. The
A right STN neuron that showed sustained activity after visual stimuli. In the delayed saccade task (lever task),
was triggered by a target cue presented on the contralateral
side and continued
until a saccade was made to the
location of the stimulus
(straight
left, as indicated with 3 dots on the left side of the raster). The activity was
saccades to other directions
were required. The directions are also indicated by the arrows on the right side of the
records arc aligned on the onset of the target cue (I&) and the onset of saccades ( @II).
VISUC)OCULOMOTOR
ACTIVITY
IN
SUBTHALAMUS
7RlON02.07/ESAC
FIG. 14. A right STN neuron showing activity
related to target and reward.
In the saccadc task [eye task ( try) ] - the
neuron was activated while the monkey
was fixating on the target point (T), but not on the central fixation point (F). No
directional
selectivity
was observed.
In the fixation task [eye task (hr~om
)], in which the monkey
was rewarded
by fixating
the central point (F), the same neuron became active during the fixation.
Note that, in these experiments.
the monkey
was
rewarded
by maintaining
fixation on the spot of light: no hand movement
was required. Figures are aligned on the onset of
the fixation point ( /I$), the of&et of fixation point (c~~cv),
and the offset of the target point (right).
Some neurons with fixation-related
activity (2/22),
or
with the target- and reward-related
activity (4/29), showed
phasic increases in discharge rate just after the fixation
point came on ( Fig. 15). To determine whether this activity
represented a visual response with a receptive field, we examined eye positions at the time of fixation point onset. We
found, however, no correlation between the retinal position
of the fixation point and the magnitude of the phasic increase in firing rate.
ACTIVITY
RELATED
TO LEVER RELEASE.
Forty-nine neurons
changed their activity in relation to the lever release. Neurons that had sensorimotor
responses were excluded from
this group. Both phasic responses ( Fig. 16) and preparatory
responses (Fig. 17) were found. Within the phasic response
category were four types: excitation before lever release
(Fig. 16A, n = 14), excitation after lever release (Fig. 16&
n = 1 I ), inhibition before lever release (Fig. 16C, n = 13),
and a combination of excitation and inhibition (Fig. 16D,
n = 7) .
Figure 17 illustrates
the response of neurons
exhibiting
preparatory activity (n = 4). This activity started > 1 s before lever release (Fig. 17, top). We found no evidence of
consistent movements in any body parts during this period.
These changes in activity were absent, however, during the
eye task (Fig. 17, hotto~n) in which the monkey fixated the
same target spots but did not release the lever. This result
suggests that the activity was specific for the hand movements per se rather than being related to reward expectancy, unlike the neurons classified above as target- and
reward-related
( see above).
AC‘TIVITY
RELATED
-I’0 ANIMAL’S
ACTIVE
MOVEMENTS
OR
PASSIVE MANIPIJLATlONS
OF THE BODY PART.
A summary
TO
of
responses related to active movements or passive manipulation is shown in Table 1. Effective stimuli were passive manipulation of joints and pressure on the muscles. Light
touch and air-blow never evoked responses. The somatosensory responses usually had wide receptive fields, although
these were confined to the contralateral side. Because our
primary concern was with the visuomotor activity of these
1626
MATSUMURA
ET AL.
FIG. 15. Complex nature of the activity related to target and reward. Sustained activity during fixation on the target point
was present during both the saccade task [lever task (top)] and the delayed saccade task [lever task (hoitmn)]. In addition,
this neuron discharged phasically after onset of the central fixation point. It also showed spike discharges before the appearance of the target point, when the monkey was presumably expecting it. Figures are aligned on onset of fixation point ( /L$),
onset of target point (caner), and offset of target point (righi).
neurons, we did not examine the characteristics
neurons in detail.
of these
DISCUSSION
Nearly 20% of the neurons recorded from the STN in the
present study became active during eye fixation or saccadic
eye movements or in response to visual stimuli. The results
suggest that STN participates in the control of visuooculomotor behavior in cooperation with other basal ganglia nuclei such as the caudate nucleus and SNr.
Topographic organization of STN
Neurons related to visuooculomotor
behaviors were
found primarily in the ventral part of STN, whereas neurons related to skeletomotor behaviors usually were located
in the dorsal part. This pattern of responses is consistent
with the differential fiber connections of the dorsal and ventral STN with the cerebral cortex and basal ganglia nuclei.
The somatomotor cortical areas (areas 4 and 6) project in a
somatotopic manner to the laterodorsal part of STN, with
face area located laterally and leg area medially. In contrast,
the ventral part of STN receives projections from the frontal association cortices (areas 8 and 9, Hartman-von Monakow et al. 1978) as well as from the frontal eye field (Huerta
et al. 1986; Stanton et al. 1988) and supplementary eye
field (Huerta and Kaas 1990).
STN is known to project to several basal ganglia nuclei.
The globus pallidus (internal and external segments) and
SNr are its two major recipient areas. Efferents from STN
seem to exhibit a ventrodorsal topography. The ventral part
of STN projects to substantia nigra and the caudate nucleus, whereas the dorsal part projects to the internal segment of the globus pallidus and putamen (Nakano et al.
1990; Parent and Smith 1987 ). A mediolateral topography
has also been suggested in the subthalamonigral connection
(Smith et al. 1990). The subthalamonigral
fibers terminate
mostly within the pars reticulata (Carpenter et al. 198 1b).
Cells related to visual and/or mnemonic-oculomotor
behaviors are found in both the SNr and the caudate nucleus
(Hikosaka and Wurtz 1983a-d; Hikosaka et al. 1989a-c).
In the following sections we will consider how each of the
VISUOOCIJLOMOTOR
ACTIVITY
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FIG. 16.
STN neurons showing different types of activity related to lever release. Figures are aligned on the time of lever
release. Increased activity before lever release (A : delayed saccade task), after lever release ( II: saccade task ) , decreased
activity before lever release ( C’: delayed saccade task ), and a combination
of excitation
and inhibition
at lever release ( II:
saccade task ) .
visuooculomotor
signals might be reorganized
through the afferent and efferent connections
or integrated
of the STN.
A significant number of the neurons studied in STN
showed sustained spike discharges during active eye fixation on task-specific
targets. This activity appeared to be
unrelated to eye position. It usually was not elicited during
eye fixations made outside the tasks. The activity decreased
when the target spot subsequently was removed. Although
the origin of this activity is uncertain, both the caudate nucleus and frontal cortical areas may be two likely candidates
by virtue of their projections to STN.
Many neurons in the caudate nucleus show sustained
spike activity while the monkey is fixating to obtain a reward (Hikosaka
et al. 1989~). The activity is unrelated to
eye position and is unrelated to spontaneous eye fixation, as
in STN. Thus the sustained excitatory signals from the caudate nucleus could be transmitted
to STN through serial
inhibitory connections via the external segment of the globus pallidus, producing a similar sustained activity in STN.
Whether the external pallidal neurons exhibit responses related to eye fixation remains to be examined.
Different parts of the prefrontal association cortex contain neurons that show sustained increases or decreases
during eye fixation on task-specific light targets. Suzuki et
al. ( 1979) were the first to characterize the types of eye
fixation-related
neurons in the inferior dorsolateral prefrontal cortex. Some neurons were shown to be dependent
on the presence of visible targets, whereas others maintained the spike activity even when the target was turned of?’
but the monkey was still fixating on the position of the
target. Joseph and Barone ( 1987) found that neurons in the
area superior to the principal sulcus showed sustained activity during eye fixation, but in a manner highly dependent
on the behavioral contexts. These prefrontal cortical neurons thus share some features in common with STN neurons.
In contrast, the possibility that the direct inputs from the
parietal cortex to STN cause the sustained STN activity is
less likely, because the activitv of parietal fixation neurons
is clearly related to eye posit&,
unlike STN neurons (Andersen and Mountcastlc
1983; Lynch et al. 1977: Mountcastle et al. 1975; Sakata et al. 1980).
The eye fixation-related
signals in STN mav be convevcd
to SNr. Although initially considered to be inhibitory (beLong and Georgopoulos
198 1; Hammond
et al. 1983b:
Larsen and Sutin 1978; Perkins and Stone 1980), STN efferent connections are now thought to be at least partlv
excitatory and may use glutamate as a neurotransmitte;
(Hammond
et al. 1978, 1983a; Kitai and Kita 1987: Na-
I628
MATSUMURA
ET AL.
120”
c
V-
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L
1
III
III
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g4
7RlON01,03/SACD
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l l l
FIG. 17. Activity
related to preparation
for
lever release. Top: activity increased after onset of the target point and ceased 200 ms before lever release (lever task; delayed saccade
task). Rasters are aligned on onset of target
point (1&) and time of lever-release
(rig&).
Bottom: activity disappeared
in the eye task in
which monkey
was required
neither to press
nor to release the lever (eye task: delayed saccade task). Rasters are aligned on onset (/<fi)
and offset (C&Y) of target point.
0
1OOms
7RlONOl.O5/ESACD
kanishi et al. 1987; Robledo and Fi3ger 1990; Rouzaire-Dubois et al. 1983, 1984; Smith and Parent 1988). The excitatory signals would be used to enhance the tonic spike activity of nigral cells, thus help maintaining
eye fixation.
Although most visuooculomotor
neurons in SNr show a
clear-cut decrease in firing during eye fixation, some neurons show a sustained, albeit less clear-cut, increase in firing
(unpublished observations).
Smmdic
activity I in STN
A group of neurons in STN showed an increase of spike
activity that was time-locked to task-specific saccades. The
changes in activity were unrelated to spontaneous saccades
made outside the task. One third of the neurons were active
predominantly during saccades made to visual targets, and
another third were active predominantly during saccades to
remembered targets. A similar feature was found in the caudate nucleus (Hikosaka et al. 1989a). For more than half of
the STN neurons, the onset of the saccadic activity preceded saccade onset, but not to a great extent. These results
suggest that saccadic information in STN could play a role
in the initiation of saccades. It seems unlikely, however,
that initiation is a major function of STN neurons, because
a dominant portion of their activity occurs after a saccade.
The saccadic activity in STN could be derived directly
from the frontal cortex or indirectly from the caudate nucleus. The frontal eye field (Huerta et al. 1986; Stanton et
al. 1988) and supplementary eye field (Huerta and Kaas
1990) are the two primary candidate cortical sites. Neurons
that have presaccadic and postsaccadic activities are found
in both areas. Neurons in these two cortical eye fields become active before purposive saccades to visual or remembered targets (Bruce and Goldbern 1985; Schlag and
VISUOOCULOMOTOR
ACTIVITY
Schlag-Rey 1987 ) . These signals may reach STN, although
the outputs from STN may occur too late to play a role in
saccade initiation.
Postsaccadic activity in these cortical
areas could also contribute to the STN activity. This appears less likely, however, because postsaccadic activity in
these regions of cortex is usually less selective, is sometimes
omnidirectional,
and may occur during spontaneous saccades, unlike neurons in STN.
The caudate nucleus contains many neurons that fire before task-specific voluntary saccades (Hikosaka
et al.
1989a). This signal could be transmitted to STN through
the external segment of the globus pallidus (Groenewegen
and Berendse 1990; Kita et al. 1983; Ohye et al. 1976; Parent 1986). The conditional nature of STN saccadic activity
appears to be very similar to the responses of caudate neurons, including those responses contingent on visually
guided saccades and those contingent on memory-guided
saccades.
If the saccadic signals present in STN are conveyed to
SNr as discussed above, we would expect a phasic increase
of SNr cell activity. However, the saccadic activity in SNr is
usually characterized by decreases in firing rate (Hikosaka
and Wurtz 1983a). There is no easy way to interpret the
discrepancy. Perhaps the summation of influences from the
STN with stronger inhibitory influences from the striatum
always results in a net inhibition of activity in the SNr. This
explanation would imply that input from the STN served
primarily to alter the excitability of SNr neurons but
usually did not result in clear increase in firing rate of most
SNr neurons. Of course, it also remains possible that the
saccade-related activity of STN neurons may not be transmitted directly to the SNr, or that perhaps these particular
projections are of an inhibitory nature.
The suppressive role of the STN in saccades may be supported by the paucity of saccadic eye movements in parkinsonian patients (Hikosaka and Wurtz 1989) and MPTPtreated primates (Usui et al. 1990), presumably both associated with increased STN activity (Bergman et al. 1990).
In contrast, the lesion of the STN would be expected to
produce an opposite effect-hyperkinesia
of the eye. However, oculomotor symptoms have been reported only in a
limited number of cases (Bedwell 1960; Martin 1927). In
our preliminary
experiments, injection of muscimol (a
GABA agonist) into the monkey STN induced a strong eye
deviation to the contralateral side in addition to ballistic
movements in the contralateral body parts. Whether this is
due to the blockade of the STN excitatory outflow remains
to be determined.
Visual response
Visually responsive neurons appear to be always present
in brain areas containing eye movement-related
neurons
(Bruce and Goldberg 1985; Bushnell et al. 198 1; Hikosaka
et al. 1989b; Hikosaka and Wurtz 1983a; Mohler et al.
1973; Robinson et al. 1978, 1986; Schlag and Schlag-Rey
1984, 1987; Wurtz and Mohler 1976), and STN is no exception to this rule. Receptive fields of visually responsive
neurons in STN were usually centered in the contralateral
hemifield, sometimes extending into the ipsilateral field.
This feature is similar to visual neurons in the caudate nucleus (Hikosaka et al. 1989b), frontal eye field (Bruce and
IN SUBTHALAMUS
1629
Goldberg 1985 ) , supplementary
eye field ( Schlag and
Schlag-Rey 1987 ), and intralaminar nuclei of the thalamus
(Schlag and Schlag-Rey 1984). As discussed for eye fixation-related activity and saccadic activity (see above), visual signals may also be directly derived from the cortical
eye fields or indirectly from the caudate nucleus. Latencies
of visual responses are usually 70- 120 ms in STN (present
study), 60- 100 ms in the frontal eye field (Goldberg and
Bushnell 198 1 ), and loo-250 ms in the caudate nucleus
(Hikosaka et al. 1989b). This would seem to preclude the
caudate nucleus as a major site of origin of STN visual
responses. Visual signals could instead reach the caudate by
the reverse connection (Nakano et al. 1990).
Many of the STN visual neurons responded best to parafovea1 stimulation,
and these changes in firing rate were
almost always increases in activity. In contrast, peripheral
stimuli, either contralateral or ipsilateral, could suppress
these neurons (e.g., Fig. 12). This effect requires wholefield integration of visual information, as postulated for neurons in a prestriate visual area ( V4, Desimone et al. 1985 ) .
This type of STN neuron could act to enhance SNr cell
activity if a visual stimulus was present close to the line of
sight, but would reduce the facilitatory effect if the stimulus
was present in the periphery. In other words, such STN
neurons would decrease or increase the probability of saccades, depending on the position of the saccade-triggering
stimuli within the visual field.
Activity related to target and reward
Target- and reward-related activity occurred only when
the monkey could expect to gain a reward by detecting the
dimming of the light spot that he was fixating. This type of
neuron showed no change in activity while the monkey was
fixating the central fixation point to start a trial if the fixation point itself was not associated with reward. Eye fixation on a light stimulus may not be prerequisite: sometimes
it started even before the target point came on (Fig. 15 ).
Similar responses were commonly seen in the caudate
nucleus (Hikosaka et al. 1989~). The sustained spike discharge of caudate neurons was present regardless of
whether the monkey obtained reward by releasing a lever,
by just maintaining fixation on the target, or by making an
appropriate saccade, all features that were also observed for
STN neurons (Figs. 14 and 15). Thus both STN and caudate neurons appear to carry information related to expectation of reward.
In the dorsomedial part of the prefrontal cortex, Rizzolatti et al. ( 1990) found neurons that showed sustained
spike activity only when the monkey fixated on an object
that he was ready to reach and grasp. No change in activity
was seen when the monkey fixated an object but refused to
reach it (e.g., a syringe). Such reward contingency appears
to be similar to that observed for STN neurons, although
the paradigms used to study the neurons were different.
Furthermore, the prefrontal activity was unrelated to eye
position, as seen in STN.
It is uncertain whether this type of activity has a motor
role. It could be related to expectation of reward, contributing to the sequence of neural events that are not directly
coupled with m otor outputs. Its motor role cannot be denied, however. It may help the eyes focused on a visual
1630
MATSUMURA
object by suppressing saccades. This would be the same
effect expected for eye fixation-related
activity, but more
emphasis here would be placed on a visual object that was
directly associated with reward. In addition, this target- and
reward-related activity might contribute to suppression of
skeletomotor behaviors, especially because the monkey
usually withheld gross movements during this period.
Function of the subthalamic nucleus
We will first consider the possible outcomes of the neural
activities in STN, given the presumed efferent connections,
and then put forward a hypothesis for the function of STN
in voluntary, purposive behaviors.
Any argument about the functions of the subthalamic
nucleus critically depends on whether its neurons are excitatory or inhibitory. On the assumption that STN neurons
are excitatory, as most recent studies suggest (Hammond et
al. 1978, 1983a; Kitai and Kita 1987; Nakanishi et al. 1987;
Robledo and Feger 1990; Rouzaire-Dubois
et al. 1983,
1984; Smith and Parent 1988), activation of STN neurons
should lead to an increase of basal ganglia efferent activity,
thus enhancing the inhibition of target structures such as
the thalamus, superior colliculus, and pedunculopontine
nucleus. The behavioral outcome of neural activity in STN
should therefore be an inhibition
of a motor outputs, at
least for eye movements. Similar proposals have been made
with respect to skeletal movements on the basis of lesions of
STN, which produce hemiballismus,
jerky involuntary
movements in contralateral body parts (Bergman et al.
1990; Carpenter et al. 1950; Carpenter 198 1; DeLong and
Georgopoulos 198 1) .
STN-mediated suppression of motor outputs may be necessary for appropriate execution of purposive behaviors.
Suppose a purposive behavior consists of a set of motor acts
organized in a particular spatiotemporal manner. The central motor systems would set up motor programs for these
motor acts, but allow only a portion of them to be activated
at a time while suppressing the others. Triggering a movement would be carried out by the removal of the suppression in a selective and sequential manner.
The subthalamic nucleus might act as an interface for
these suppressive mechanisms. The mechanisms could be
activated directly by the frontal cerebral cortices through
corticosubthalamic
connections, or indirectly through
striato external pallidal subthalamic connections. The suppression should be specific, highly contingent on the behavioral contexts, and could be predictive on the basis of the
motor plan. Interestingly, the basal ganglia also possess an
opposing mechanism: striato-nigral/ internal pallidal connections, which would facilitate the target motor areas by
disinhibition
(Chevalier and Deniau 1990; Hikosaka and
Wurtz 1989; Mink and Thach 199 1). The disinhibitory
mechanism would be at work for the initiation of movements, as seen for presaccadic neurons in the caudate nucleus (Hikosaka et al. 1989a) and SNr (Hikosaka and
Wurtz 1983a,b). The subthalamic suppressive mechanism
would act to maintain eye position on an object of interest
or recover eye fixation once a saccade is executed (this
study).
Note that the above argument is based on the assumption
that STN neurons transmit signals by increasing their activ-
ET AL.
ity. In fact, we occasionally observed decreases in activity,
which would lead to an opposite effect. Furthermore, the
possibility still remains that neurons in the STN are heterogeneous in synaptic action and that some of them may exert
inhibitory effects on their target neurons.
We express our deep appreciation to Prof. Chihiro Ohye for discussing
the earlier results of these experiments. We thank M. Nakanishi and Dr. H.
Tokuno for their help with histology, L. Bertrand, M. Togawa, and 0.
Nagata for their help in preparation of figures, Dr. M. Kato for designing
the computer programs, and Drs. P. Bedard, M. Filion, and A. Parent for
reviewing the manuscript. Thomas W. Gardiner was on leave from the
University of Tennessee, Memphis, TN.
Address for reprint requests: 0. Hikosaka, National Institute for Physiological Sciences, 38 Nishigonaka, Myodaijcho Okazaki, 444, Japan.
Received 8 July 199 1; accepted in final form 17 January 1992.
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