Download Neuroanatomical correlates of the near response: voluntary

European Journal of Neuroscience, Vol. 12, pp. 311±321, 2000
ã European Neuroscience Association
Neuroanatomical correlates of the near response:
voluntary modulation of accommodation/vergence in the
human visual system
Hans O. Richter,1,2,3,* Joel T. Lee,3 and Jose V. Pardo3,4
1
Brain Sciences Center, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA
Department of Physiology, University of Minnesota, Minneapolis, MN 55455, USA
3
Cognitive Neuroimaging Unit, Psychiatry Service, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA
4
Division of Neuroscience Research, Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455, USA
2
Keywords: attention, brain blood ¯ow, brain mapping, frontal eye ®eld, saccade, smooth pursuit
Abstract
This study identi®es brain regions participating in the execution of eye movements for voluntary positive accommodation (VPA)
during open-loop vergence conditions. Neuronal activity was estimated by measurement of changes in regional cerebral blood ¯ow
(rCBF) with positron emission tomography and 15O-water. Thirteen naive volunteers viewed a checkerboard pattern with their
dominant right eye, while a lens interrupted the line of gaze during alternate 1.5 s intervals. Three counterbalanced tasks required
central ®xation and viewing of a stationary checkerboard pattern: (i) through a 0.0 diopter (D) lens; (ii) through a ±5.0-D lens while
avoiding volitional accommodation and permitting blur; and (iii) through a ±5.0-D lens while maintaining maximal focus. The latter
required large-amplitude, high-frequency VPA. As an additional control, seven of the subjects viewed passively a digitally blurred
checkerboard through a 0.0-D lens as above. Optometric measurements con®rmed normal visual acuity and ability to perform the
focusing task (VPA). Large-amplitude saccadic eye movements, veri®ed absent by electro-oculography, were inhibited by central
®xation. Image averaging across subjects demonstrated multifocal changes in rCBF during VPA: striate and extrastriate visual
cortices; superior temporal cortices; and cerebellar cortex and vermis. Decreases in rCBF occurred in the lateral intraparietal area,
prefrontal and frontal and/or supplementary eye ®elds. Analysis of regions of interest in the visual cortex showed systematic and
appropriate task dependence of rCBF. Activations may re¯ect sensorimotor processing along the re¯ex arc of the accommodation
system, while deactivations may indicate inhibition of systems participating in visual search.
Introduction
The principal stimulus triggering accommodative responses (AR)
under typical viewing conditions is blur. Blur provides ambiguous
information by lacking directionality in focusing power, i.e. no direct
information about the over- or under-focusing of a target. Yet, the
visual system is exquisitely sensitive to dioptric blur (Legge et al.,
1987). Secondary cues (e.g. chromatic aberration) must be processed
in parallel within a short time period and combined with the early
computations of blur. Full posturing of the AR upon a target requires
at least 350 ms following the detection of blur (Toates, 1972). During
this time, computations include preliminary target identi®cation and
the initiation of AR.
The process by which the dioptric error becomes transformed into
a motor command for accommodation remains largely unknown. The
motor effector consists of ciliary muscles regulating both pupillary
diameter and the curvature of the eye-lens. Autonomic parasympathetic ®bres from the Edinger±Westphal nucleus innervate the ciliary
Correspondence: Dr J. V. Pardo, Cognitive Neuroimaging Unit (11P), VAMC,
One Veterans Drive, Minneapolis, MN 55417, USA. E-mail: [email protected]
*Present address: PET Centrum, Uppsala Universitet, UAS 75185, Uppsala
and Department of Ophthalmology, Karolinska Institute, Huddinge Hospital,
Huddinge, Sweden.
Received 9 April 1999, revised 31 August 1999, accepted 14 September 1999
muscle (Fig. 1A). However, the eye does not adjust focus based upon
a simple interaction between the blur signal and autonomic tonus. For
example, stimulus sources can produce variation in the AR
independent of retinal contrast (Westheimer, 1957; Provine &
Enoch, 1975; Malmstrom & Randle, 1976; Ciuffreda & Kruger,
1988; McLin & Schor, 1988; McLin et al., 1988; Takeda et al., 1990;
Richter & FranzeÂn, 1994). Structural correlates to these `higherorder' effects upon the AR re¯ex remain unmapped in humans. In
sum, cortical processes preceding and monitoring the ciliary motor
command signal are poorly understood (Fig. 1B).
Several literature reports detail rapid learning and execution of
volitional increases in dioptric strength of the crystalline eye lens, or
voluntary positive accommodation (VPA, Campbell & Westheimer,
1960; Provine & Enoch, 1975; Ciuffreda & Kruger, 1988; McLin &
Shor, 1988). Campbell & Westheimer (1960) measured VPA up to
3.0 D using a continuous recording optometer. Provine & Enoch
(1975) successfully trained subjects to generate 9.0 D VPA to nullify
the effects of a ±9.0-D contact lens. Ciuffreda & Kruger (1988)
quanti®ed and compared re¯exive accommodation and VPA; both
exhibited similar rates of change (diopters per second).
The experiments presented here test the hypothesis that VPA
movements of the eye involve neural circuits which can be visualized
in healthy humans with positron emission tomography (PET)
neuroimaging. Speci®cally, the present aim was to identify brain
312 H. O. Richter et al.
FIG. 1. (A) Human dioptric focusing system and efferent pathways from the autonomic nervous system (ANS) to the ciliary muscle. The major innervation to the
ciliary muscle is parasympathetic and follows the pathway shown by the thick solid lines. The parasympathetic pathway originates in the Edinger±Westphal
nucleus and courses with the third nerve, where the ®bres travel to and synapse in the ciliary ganglion. The majority of the postganglionic parasympathetic ®bres
travel to the ciliary muscle via the short ciliary nerves, but some of them (double asterisk) also travel with the long ciliary nerves. There is also evidence for a direct
pathway of uncertain functional signi®cance (single asterisk) to the internal eye structures from the Edinger±Westphal nucleus. The sympathetic supply to the
ciliary muscle (thin solid lines) originates in the diencephalon and travels down the spinal cord to the lower cervical and upper thoracic segments, to synapse in the
spinociliary centre of Budge in the intermediolateral tract of the cord. From there, second-order nerves leave the cord by the last cervical and ®rst thoracic ventral
roots; these preganglionic ®bres run up the cervical chain to synapse in the cervical ganglion. The third-order ®bres continue up the sympathetic carotid plexus and
enter the orbit, either with the ®rst division of the trigeminal nerve (following the nasociliary division) or independently, where they join the long and short ciliary
nerves, in the latter instance passing through the ciliary ganglion without synapse. Note that the connections between these pathways and the cerebral cortex are
unspeci®ed. C8, cervical vertebra 8; T1, thoracic vertebra 1; T2, thoracic vertebra 2. (reproduced with permission from Kauffman, 1992). (B) Schematic model of
accommodative processing during monocular viewing. When an image of a visual target on the retina is blurred, ~ 500 ms elapse between the detection of the
blurred target and the complete AR to the target. During this time, neural circuits probably in the cerebral cortex and cerebellum compute the location of the
intended target, decide whether to focus upon the intended target, and initiate the AR. Iterative computations tune the AR based upon initial visual sensory cues,
feedback and comparison with the internal representation of the target. Open loop vergence in the viewing eye is inhibited. During visual accommodation top±
down, cognitive-perceptual processing occurs within the accommodative system.
activity with the process of accommodation (and secondary re¯ex
vergence), not with the degree or precision of accommodation.
Changes in neuronal activity, indexed by changes in regional
cerebral blood ¯ow (rCBF), were measured across tasks with PET
and the bolus 15O-water method. Three control conditions were used
to evaluate the effects of blurring and contrast adaptation. The
changes in rCBF were averaged after anatomical standardization
across subjects. The resultant images identify putative networks
involved in VPA and provide testable hypotheses for future research.
Some ®ndings from this study have been presented previously in
abstracts (Pardo et al., 1995; Richter et al., 1995).
Materials and methods
Subjects
Thirteen naive healthy subjects (seven females and six males; mean
age of 27 years, SD 66; range 20±43; all but one right-handed)
participated in the PET study. Optometric measurements con®rmed
normal visual acuity and ability to perform the focusing task (VPA).
The volunteers gave written informed consent according to guidelines
of the Institutional Review Board and the Radioactive Drug Research
Committee.
Behavioural paradigm and task analysis of VPA
Four counterbalanced conditions provide contrasts between oculomotor processes during VPA: (i) stable (steady-state) visual
accommodation through a 0.0-D glass lens (No-blur; Fig. 2A); (ii)
inhibition of accommodation to blur induced optically by a ±5.0-D
glass lens (Opt-blur; Fig. 2B and D): the subjects see alternately a
sharp or a blurred image; (iii) VPA requiring large amplitude (~ ±
5 D), high-frequency (0.3 Hz), voluntary positive accommodation in
the viewing eye in response to a retinal image defocused by a ±5.0-D
lens (VPA; Fig. 2C) ± the subjects see mostly a sharp image, and the
occluded eye shows synergistic accommodative/vergence movements
(Fig. 2E); and (iv) passive viewing through a 0.0-D lens a checkerboard pattern blurred digitally to ~ ±5.0 D (Dig-blur) ± the subjects
see a blurred image at all times. The resultant dioptric stimulus levels
were as follows: 2.5 D for the No-blur condition; 7.5 D for the Optblur viewing condition; 2.5±7.5 D for the VPA condition; and 2.5 D
for the Dig-blur condition.
The subjects' non-dominant eye (i.e. left eye) was patched. They
®xated monocularly with the dominant eye upon a cross in the centre
of a black and white monochromatic checkerboard pattern displayed
on a video monitor 40 cm away (described below). In Opt-blur and
VPA, the checkerboard pattern was blurred by manually placing a ±
5.0-D lens in front of the single naked (or corrected) eye for 1.5 s
followed by removing the lens for 1.5 s. An electronic timer signalled
the experimenter to change the lens position every 2 s. The same
presentation procedure was followed for No-blur and Dig-blur except
for the substitution of a 0.0-D lens. During VPA, the blurred image
was brought into focus following each lens insertion by VPA.
Instructions can bias the AR to sine wave gratings (Ciuffreda &
Hokoda, 1985). The instructions used here were adapted from Stark
& Atchison (1994): No-blur, `look at the checkerboard naturally ± the
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
PET study of human voluntary visual accommodation
313
same as you would when viewing a book or a sign at the same
distance ± and maintain ®xation'; Opt-blur and Dig-blur, `look at the
checkerboard ± make no effort to focus on it when the lens is placed
in front of the eye ± let the checkerboard remain blurry and maintain
®xation'; and VPA, `look at the checkerboard and after each repeated
defocus condition, carefully focus on the checkerboard so that it is
maximally sharp and clear at all times ± maintain ®xation.'
conditions, one of the subjects studied with PET underwent detailed
measurement of eye movements in the Eye Movement Laboratory of
the Department of Ophthalmology, Karolinska Institute (courtesy of
Dr Han Ying). Eye movements under the different task conditions
were measured using an infrared eye-tracker (Ober-2, Permobil,
Sweden).
Eye movement recording
The black and white checkerboard (~ 1 cycle per degree) subtended
10.74° and contained a central ®xation cross (1.5°) to inhibit saccadic
eye movements and to disable drifts in smooth pursuit. The display
monitor was stationary, and there was no change in proximal stimulus
for the conditions. The VPA responses occurred under dim lighting
conditions. Space average luminance was 37.5 cd/m2 for the video
screen and 1.0 cd/m2 for the surround (Quantum Instrument,
Photometer LX, Garden City, NJ, USA).
The digitally blurred checkerboard pattern was designed to appear
subjectively similar to the optically blurred checkerboard (i.e. when
viewed without accommodative effort through a ±5.0-D lens). Digital
blurring was achieved by applying to the image of the checkerboard
with ®xation mark a two-dimensional Gaussian ®lter with full-width
at half-maximum (FWHM) of 2.8 mm (i.e. 4 pixel radius; pixel size
0.35 3 0.35 mm) in Adobe Photoshop V 4.0 (Adobe, San JoseÂ, CA,
USA).
During scanning, the absence of large amplitude saccades away from
®xation was monitored visually and with electro-oculograms
(Coulbourn S75-01 Bioampli®er, Allentown, PA, USA; saccade
detection sensitivity of ~ 5°). To ensure that the tasks elicited the
expected eye movements during VPA and during the control
Visual stimuli and effects of dioptric defocus
PET scanning and image processing
PET scans were acquired on an ECAT 953B camera (Siemens,
Knoxville, TN, USA) in two-dimensional mode without correction
for scatter or decay. Images contain 31 axial slices spaced ~ 3.5 mm
apart. Subjects had an intravenous line in a forearm vein. Their head
position was stabilized with a vacuum-moulded pillow (Olympic Vac
Pac Medical, Seattle, WA, USA). Production and delivery of H215O
were automated (Palmer et al., 1995). Approximately 1480±
1850 MBq (40±50 mCi) of H215O in 10 cc of normal saline was
injected as a bolus over 10 s (Herscovitch et al., 1983). Tasks began
~ 15 s before tracer injection. Ten minutes elapsed between scans to
allow decay. Changes in normalized tissue activity, integrated over
60 s after arrival of radioactivity into the brain, were used as an
estimate of changes in rCBF. Data acquired with a zoom factor of
1.25 were reconstructed with ECAT software using ®ltered back-
FIG. 2. Experimental design for neuroimaging of monocular VPA. (A) The
No-blur condition involved maintaining ®xation while a 0.0-D lens was intermittently placed in front of the dominant eye. (B) The Opt-blur condition
required the subject to avoid focusing upon the checkerboard whenever a ±
5.0-D lens intermittently interrupted the line of sight. The AR is inhibited
volitionally and the retinal image remains blurred. (C) The condition of voluntary positive accommodation (VPA) required the subject to maintain
maximal focus upon the checkerboard whenever the ±5.0-D lens interrupted
the line of sight. High-frequency (0.3 Hz), large-amplitude (~ +4.5 D), voluntary AR must occur for successful performance. A compatible distribution
of negative AR results after the removal of the ±5.0-D-lens, after each successful VPA response. One additional control (not shown) included passive
viewing of a digitally blurred checkerboard (Dig-blur). (D) Typical amplitudes of horizontal eye movements during Opt-blur. Note the absence of
large-amplitude, synkinetic vergence eye movements of the occluded left
eye (contrast with E below) and stable ®xation of right eye. RE, right eye
position; LE, left eye position. Downward de¯ection denotes eye movement
to the right. (E) Typical amplitudes of horizontal eye movements during
VPA to a ±5.0-D blurred checkerboard. Co-activation of vergence in the left
(occluded eye) during VPA is obvious (mean 6 SD, 8.26 6 1.19). Although
most vergence in the ®xating right eye is inhibited, small order conjunctional divergence movements to the right can be observed (mean 6 SD,
0.74 6 0.27). LE, RE, and eye movement conventions as in D.
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
314 H. O. Richter et al.
projection with a Hann ®lter of 0.4 cycles/pixel. The ®nal ®ltered
image resolution was 11 mm FWHM. Software developed by
Minoshima and colleagues (Minoshima et al., 1992; 1993; 1994)
normalized global activity within each scan, realigned scans within a
study session, estimated the intercommissural line from image
®ducials, and transformed stereotactically the data using linear
warping. ANALYSETM (BIR, Mayo, Rochester, MN, USA)
permitted further image processing and display.
pupillary constriction/dilatation. Blur-driven accommodation signals
in¯uence vergence output, and similarly, disparity-driven vergence
signals in¯uence accommodation output. We chose to study blurdriven accommodation with vergence disparity under open-loop
conditions (i.e. monocular viewing), thereby, maximally stressing the
accommodation subsystem and leaving the vergence system devoid
of sensory input.
Signi®cance threshold selection
To explore the functional anatomy of voluntary accommodation
processes across the whole brain, analyses of paired image
subtraction were completed for the following three contrasts: (i)
VPA minus No-blur; (ii) VPA minus Opt-blur; and (iii) VPA minus
Dig-blur. Two scans were obtained from each subject for these three
conditions (No-blur, Opt-blur, VPA). Seven of the subjects also
contributed one scan of Dig-blur. Task order was counterbalanced
whenever possible across subjects.
Comparison of No-blur and Opt-blur did not reveal signi®cant
omnibus differences (i.e. 0 pixels above a P < 0.001 threshold, with
89 pixels expected by chance). Therefore, this image subtraction was
not signi®cantly different from image noise and was not further
analysed. Comparing the VPA with control conditions, No-blur or
Opt-blur, showed signi®cant differences (VPA minus No-blur had
187 pixels above a P < 0.001 threshold, 88 pixels expected from noise;
VPA minus Opt-blur had 793 pixels, 88 pixels expected). Likewise,
VPA differed signi®cantly from Dig-blur (149 pixels observed,
96 expected).
Hence, high-frequency (0.3 Hz), large-amplitude (~ +4.5 D) monocular accommodation to a blurred checkerboard pattern produces
signi®cant changes in rCBF when compared with all control
conditions (No-blur, Opt-blur and Dig-blur). These activations along
with their stereotactic coordinates appear in order of decreasing
magnitude in Table 1a±f. Figure 3 displays activations and deactivations in the contrast between VPA and No-blur.
ROI analysis
Occipital activation during VPA
Because the quality of the sensory representation plays a critical role
in accommodative processing, unsubtracted or subtracted rCBF
(DrCBF) in the visual cortex was assessed across the different scan
conditions. Repeated-measures ANOVA was performed on individual
activity in spherical ROIs in calcarine (~ 8 mm radius) or occipital
(~ 16 mm radius) cortex. Bilateral ROIs were centred on the Talairach
coordinates (+17, ±94, ±7) in BA 17 or (+17, ±87, 0) including BA 18
and 19.
Additional spherical ROIs (~ 8 mm radius) were centred on the
coordinates of peak subtracted rCBF (DrCBF) resulting from VPA
minus either No-blur or Opt-blur. The Talairach coordinates that
guided these ROIs appear in Table 1a±d. Pearson product moment
correlations were next calculated to provide a common metric for
displaying the relation between activity in the different ROIs. By
cancelling sources of variance unrelated to VPA, the between-task
DrCBF matrix shows a commonality in how structures become
activated or deactivated during the production of VPA (for details of
methodology, see Zald et al., 1998b).
A distributed set of activation foci in occipital visual cortex (BA 17
and 18) appeared during VPA in comparison with all control
conditions (see Table 1) Visual regions included the posterior portion
of the calcarine cortex subserving the fovea, lingual and fusiform
gyri, and cuneus. The visual responses show left hemispheric
dominance.
A signi®cance threshold of Z = 3.2 was used. This threshold is
consistent with the reported literature given the methods, sample size
and image resolution employed in this study. Non-parametric
bootstrap analysis of intrasubject contrasts between ECR scans
suggests that, on average, one false positive arises by chance in an
averaged image (Zald et al., 1998a).
Study design and contrasts
Results
Eye movements
Generally, subjects found the VPA task easy to perform. Visual
monitoring and electro-oculograms during the PET scans con®rmed
ongoing ®xation. Outside the scanner, higher sensitivity measurements in a typical subject using an infrared eye-tracker demonstrated,
during VPA, the expected synergistic vergence eye movements
(accommodative/vergence) of the occluded eye (LE) with concomitant small amplitude (0.25±1°) eye movements in the viewing eye
(RE; Fig. 2E). No large amplitude eye movements occurred in the
control conditions; eye position was stable and task appropriate
(Fig. 2D; Ditchburn, 1973). The accommodative and vergence
subsystems are tightly cross-coupled (Mays & Gamlin, 1995); an
AR is normally followed by vergence movements of the eyes and
Overall comparisons across viewing conditions
ANOVA
This analysis was restricted to the principal conditions of interest
(No-blur, Opt-blur and VPA), each with 13 subjects. The repeatedmeasures ANOVA of average rCBF in the calcarine ROI (sphere,
~ 8 mm radius; Fig. 4A) in a 3 3 2 (scan conditions 3 hemisphere)
design revealed a signi®cant main effect of scan condition
(F2,24 = 5.7, P = 0.009) and a signi®cant scan-condition±hemisphere
interaction (F2,24 = 4.0, P = 0.03). The hemisphere main effect was not
signi®cant (F1,12 = 0.2, P = 0.7). Post hoc testing with two-tailed ttests with Bonferroni correction for multiple comparisons shows that
the hemisphere activity during VPA was signi®cantly greater than
during No-blur (t12 = 3.6, P = 0.02) and Opt-blur (t12 = 3.6, P = 0.02,
see Fig. 4B). Figure 4C displays rCBF for the BA 17 region of interest
(ROI, averaged across hemispheres) for each subject and for each
condition. Overall, averaged rCBF was greater during VPA than
during Opt-blur or No-blur.
Contrasting visual responses between Opt-blur and Dig-blur
Contrast adaptation may confound the contrast between VPA versus
No-blur or Opt-blur. In No-blur, the subject sees a sharp and
unchanging checkerboard that can result in contrast adaptation. In
Opt-blur, the subject sees alternately blurred and sharp checkerboards, respectively. In VPA, the subject initially sees the same
stimuli as in No-blur, but then sees transients that could spare contrast
adaptation. However, contrasting No-blur and Opt-blur did not
produce signi®cant changes in rCBF (see above). Also, the worst case
scenario for contrast adaptation, Dig-blur, did not produce visual
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
PET study of human voluntary visual accommodation
315
FIG. 3. Cerebral activation and deactivation during voluntary positive monocular accommodation (VPA). Regions activated by the VPA response (VPA minus Noblur comparison) are shown in A (horizontal slices) and B (surface rendering of activations along lateral, medial, frontal and posterior aspect of each hemisphere).
Activation during VPA compared with No-blur. Threshold for these images set at Z = 2.1 to display optimally the pattern of activity; note that signi®cance threshold
was set at Z = 3.2. Hotter colours denote greater Z scores; white set to maximum in each image. Panels show that VPA is associated with posterior activations in
occiput and cerebellum. The visual hemispheric responses appear asymmetric. (C) (No-blur±VPA). Deactivation during VPA, condition VPA, compared with
condition No-blur. VPA, when compared with this control condition, results in deactivations in anterior structures, prefrontal cortices and medial frontal cortex at
the cingulate sulcus. Activation in many of these regions has been reported during eye movements (see Discussion).
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
316 H. O. Richter et al.
rCBF responses any different from those arising in Opt-blur
(unpaired t-test: for left hemisphere ROI, t18 = 0.4, P = 0.7; for right
hemisphere ROI, t18 = 0.34, P = 0.7).
Inter-hemispheric occipital correlations
Data from the occipital ROI (~ 16 mm radius) were used to measure
the functional connectivity between homologous visual regions
across hemispheres. A signi®cant correlation was obtained during
No-blur (r = 0.54, P = 0.056; Fig. 5A) and during VPA (r = 0.62,
P = 0.02; Fig. 5B). The visual activations arising in the contrast
between VPA and Opt-blur (see Table 1c; Fig. 6) were markedly
intercorrelated (r = 0.86, P = 0.0001), suggesting functional interactions (Zald et al., 1998b).
Hemispheric asymmetries
Figure 3 suggests dominance of the left hemisphere during VPA. The
ANOVA using the small ROI shown in Fig. 4A showed no main effect
of hemisphere. ANOVA using the larger sphere (~ 16 mm radius,
Fig. 4A) extending into the occipital activation foci of Fig. 3
demonstrates a main effect of hemisphere (F1,24 = 11, P = 0.003)
with greater activation in the left hemisphere. These asymmetries in
occipital rCBF appear even at the level of individual subjects and
even during No-blur (see Figs 5 and 7). The degree of left hemisphere
dominance for nine subjects during No-blur averaged 8% (range 4±
11%, SD 2.7), whereas the right dominance for the remaining four
subjects averaged 4% (range 3±6%, SD 1.0).
Temporal activation during VPA
Activity in the right temporal region (BA 22) was greater during VPA
than during Opt-blur (Table 1c, region 3). In the comparison between
VPA and No-blur, the same area was activated, but failed to reach
conservative levels of signi®cance (Z = 2.8). Right BA 22 had
signi®cant (P < 0.05) functional connectivity with several regions that
surfaced in the contrast between VPA and Opt-blur: right BA 17; left
BA 18; thalamus; and right basal ganglia (see Table 1c).
Cerebellar activation during VPA
Increases in cerebellar rCBF arose consistently across all the
comparisons between VPA and control conditions. These localized
TABLE 1. Brain regions implicated in voluntary positive accommodation (VPA)
Talairach coordinates
Foci
x
(a) Regions activated by the VPA response (VPA minus No-blur comparison)
1. Right striate visual cortex (BA 17)
19
2. Anterior lobe of vermis
8
3. Left visual cortex (BA 17)
±10
4. Anterior lobe of vermis
3
5. Left visual cortex (BA 18)
±6
(b) Regions deactivated by the VPA response (comparison of No-blur with VPA)
1. Left superior frontal gyrus (BA 10)
±15
2. Right frontal lobule (BA 6)
26
3. Left/right posterior cingulate
±3
4. Left parietal lobule (BA 39/40)
±35
(c) Regions activated by VPA, as shown by the VPA minus Opt-blur comparison
1. Right primary visual cortex (BA 17)
17
2. Left visual cortex (BA 18)
±17
3. Right lateral temporal sulcus (BA 22)
60
4. Thalamus (midbrain)
±1
5. Right lenticular nucleus (basal ganglia)
33
6. Right lateral cerebellum
26
(d) Regions deactivated by the VPA response (comparison of Opt-blur with VPA)
1. Left superior frontal gyrus (BA 10)*
±15
(e) Regions activated by the VPA response (VPA minus Dig-blur comparison)
1. Right lateral cerebellum
12
2. Right lateral cerebellum
33
3. Left insula
±33
4. Left primary visual cortex (BA 17)
±3
5. Right primary visual cortex (BA 17)
8
6. Left visual cortex (BA 18)
±33
7. Left lateral cerebellum
±1
(f) Regions deactivated by the VPA response (Dig-blur minus VPA comparison)
1. Left superior frontal gyrus (BA10)
±8
2. Left lateral cerebellum
±44
3. Left cingulate sulcus (BA 32)
±6
4. Left lateral cerebellum
±26
5. Right cingulate sulcus (BA 24/32)
1
6. Right frontal lobule (BA 8)
17
7. Left post central gyrus (BA 1/2)
±57
8. Left frontal lobule (BA 8)
±26
Magnitude of
peak activation
(Z-score)
y
z
±89
±67
±76
±69
±85
±7
±2
14
±16
20
4.35
3.94
3.54
3.22
3.20
62
±4
±55
±46
25
45
29
32
±5.09
±3.85
±3.48
±3.40
±94
±80
5
±8
±10
±73
±7
±9
4
0
±2
±27
5.16
4.29
3.44
3.40
3.32
3.22
62
25
±4.27
±85
±87
21
±91
±91
±76
±69
±9
±9
2
7
±2
0
±34
3.95
3.87
3.58
3.50
3.40
3.35
3.22
64
±67
50
±82
35
19
±22
26
18
±38
14
±32
±4
43
40
47
±6.15
±4.14
±3.83
±3.77
±3.63
±3.24
±3.24
±3.22
Response magnitudes and locations in coordinates of the atlas of Talairach & Tournoux (1988). x, y and z (in mm) correspond to right±left, anterior±posterior
and superior±inferior dimensions of the brain. Right, anterior and superior sides have positive coordinates. BA refers to approximate Brodmann areas. Foci at
the brain margin are labelled by an asterisk.
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
PET study of human voluntary visual accommodation
317
both to the vermis (e.g. Table 1a, regions 2 and 4) and to the
cerebellar cortex (e.g. Table 1c, region 6).
Insular activation during VPA
The only insular activation surfaced in the contrast between VPA
minus Dig-blur (Table 1e, region 3). The insula was also weakly
activated in the contrast between VPA and Opt-blur (not shown). Of
note, both of these control conditions (i.e. Opt-blur and Dig-blur) do
not require accurate posturing of the ciliary muscle to perform the
task.
Frontal and parietal deactivation during VPA
The activity of the right premotor area BA 6 (frontal eye ®eld, FEF)
was signi®cantly reduced during monocular VPA responses in the
comparison involving VPA and No-blur (Table 1b, region 2). This
decrease was highly correlated (r2 = 0.65, P < 0.001) with a
concomitant activity decrease in the left parietal lobule BA 39/40
(Table 1b, region 4; Fig. 8). Left BA 10 demonstrated deactivation in
the contrasts VPA minus No-blur; VPA minus Opt-blur; and VPA
minus Dig-blur (Table 1b, region 1, 1d, and 1f, region 1). The
contrast VPA minus Dig-blur revealed deactivations in the left
cingulate sulcus (BA 32) and in bilateral BA 8 (Table 1f, regions 3, 5,
6 and 8). No changes localized to that region of the right anterior
cingulate cortex critical to the anterior attention system (Pardo et al.,
1990).
No parietal activation was observed during VPA minus any of the
controls. A posterior cingulate deactivation mapped to BA 31 in VPA
minus No-blur (Table 1b, region 3). Also, left BA 40/39 (supramarginal gyrus; inferior parietal) was deactivated in VPA minus No-blur.
This response appeared functionally connected to the BA 6
deactivation in VPA minus No-blur (Fig. 8).
Discussion
To the best extent possible, the major source of activation in the
present study relates to VPA, and to a lesser extent, synkinetic
vergence movements. Activations may overall re¯ect sensorimotor
processing along the re¯ex arc of the accommodation system, while
deactivations may indicate inhibition of systems participating in the
visual search. However, the activity of some `near±far' neurons in the
central nervous system (neurons which are activated by visual
accommodative-vergence eye-movements) may still process both
vergence and accommodation information regardless of whether or
not these movements arise during normal viewing conditions, during
blur-driven monocular viewing (open-loop vergence; present study),
or during disparity-driven viewing (open-loop accommodation;
Zhang & Gamlin, 1998).
Occipital activity during VPA
FIG. 4. (A) Horizontal and sagittal sections of Talairach brain showing
placement of occipital and calcarine ROI (centred on x, y, z = +17, ±87, +1
and +17, ±94, ±7, respectively). (B) Group mean unsubtracted activity (rCBF)
within bilateral ~ 8 mm diameter ROI centred on calcarine sulcus (BA 17)
during controls (No-blur and Opt-blur) and during VPA. Data are
mean 6 SEM. Paired t-test, *P < 0.05, **P < 0.01. (C) Mean individual
unsubtracted activity (rCBF) within bilateral ~ 8 mm diameter sphere ROI
centred on calcarine sulcus (BA 17) during two controls and during VPA.
The blurring by ±5.0 D (~ 20/200 or 0.1 in visual acuity, Stein et al.,
1987) relative to No-blur resulted in ~ 4% change in calcarine rCBF.
Demer et al. (1993) reported that optical blur corresponding to visual
acuity reductions from 20/20 to ~ 20/200 reduced relative glucose
metabolism in the primary visual cortex by ~ 8%. However, the blur
in Demer (1993) was constant rather than the ON/OFF mode used in
the current study; this may explain the lower value of the present
study. BA 19 was noticeably less affected than BA 17 and 18 by the
dioptric manipulations in both studies.
The visual activations in BA 17 from the contrast between VPA
and Opt-blur (Table 1c) were expected and resulted in part from
increased retinal contrast during successful VPA. The increased
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
318 H. O. Richter et al.
FIG. 5. Test of hemispheric coupling of
individual unsubtracted activity (rCBF) using
the occipital ~ 16 mm spherical ROI during one
control (No-blur) and during VPA.
FIG. 6. Individual DrCBF increases from voluntary positive accommodation
minus an optically blurred reference state (i.e. VPA±Opt-blur) in right primary
visual cortex (BA 17) coupled with simultaneous increases in left visual cortex
BA 18. The Talairach co-ordinates (x, y, z) for these ROI are listed in Table 1c
(regions 1 and 2).
visual activation during VPA compared with No-blur (Table 1a; Figs 3
and 4) cannot be explained so readily. Even if the subjects were
completely accurate in their accommodation (an unrealistic view), no
activation during VPA over that in No-blur would be expected based
upon considerations of retinal contrast. Degradation of the retinal
image by dioptric defocus decreases the amplitude of the component
in visual evoked potentials dependent upon contrast (FranzeÂn et al.,
1994). In No-blur, the visual target was always in focus.
Visual cortical cells rapidly decrease their ®ring rate in
response to decreasing frequency of stimulation (Fox & Raichle,
1984). The visual activation arising during VPA versus No-blur
could theoretically occur from contrast adaptation in No-blur.
However, VPA and Opt-blur should not differ in the extent of
contrast adaptation. Dig-blur, a worst case scenario for contrast
adaptation, did not produce signi®cant visual activity when
compared with Opt-blur. Thus, contrast adaptation effects appear
minimal in the present protocol.
The occipital activation observed during VPA (Table 1a and
Fig. 3A and B) may arise from a variety of sources. (i) Hardwired,
local re-entrance within microcircuitry analogous to servo-mechan-
FIG. 7. Test of the degree to hemispheric symmetry of unsubtracted activity
(rCBF) within ~ 16 mm diameter ROI centred on the occipital lobule in both
hemispheres during one control (No-blur) and during VPA. Talairach
coordinates: x, y, z = +17, ±87, +1). Data are mean 6 SEM. n = 13. Paired ttest, *P < 0.05, **P < 0.01.
isms. Even-error and odd-error focusing signals may form at an early
stage within the visual cortex; the occipital activation reported here
may in part be a consequence of ascending (`intended value') and
descending streams (`actual value') of sensory information (Ullman,
1995). (ii) Cognitive `top±down' processing (e.g. Fulton, 1928;
Kosslyn et al., 1993; Motter, 1993; Heinze et al., 1994). (iii)
Feedforward gain control by eye position signals on activity of
striate neurons (Trotter & Celebrini, 1999).
Although the present experiment did not entail switching the
viewing eye, the hemisphere laterality effects seen in the current
study are consistent with past reports. Demer et al. (1988) used a
strobe light ¯ashing at 8 Hz while the subjects wore their distant
refractive correction during a monocular viewing condition. They
reported that the hemisphere contralateral to the viewing eye was
more active (5±20% difference) in both amblyopes and emmetropes. Also, Hung et al. (1990) quanti®ed cerebral activity with
SPECT during monocular stimulation of either eye and reported
contralateral dominance for each eye (cf. Imamura et al., 1997).
Temporal activity during VPA
Both the VPA versus No-blur and VPA versus Opt-blur image
subtractions showed regions of activation in the right or left superior
temporal regions. To some extent, these differences relate to the
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
PET study of human voluntary visual accommodation
319
PET study (Richter et al., 1998), however, adjacent BA 6 coordinates
were also deactivated bilaterally during the execution of monocular
negative voluntary accommodation.
In sum, the ocular near response could interact functionally with
the ®xation system to inhibit visual search for the purpose of
providing a clear foveal image. Evidence in favour of this hypothesis
was forwarded by Ohtsuka & Sato (1996). They presented
electrophysiological and anatomical results linking omnipause
activity (Munoz & Wurtz, 1993) with accommodation activity within
the rostral superior colliculus (see also Sawa & Ohtsuka, 1994).
Insular activation during VPA
The insular activation in VPA versus Dig-blur (and to a lesser extent
VPA versus Opt-blur) occurred under control conditions with the least
recruitment of the ciliary muscle. Insular cortices play an important
role in multimodal sensory integration and in autonomic processing
(Augustine, 1996).
Parietal deactivation during VPA
choice of threshold. However, inhibition of re¯ex accommodation
may have occurred in Opt-blur, possibly contributing to the change in
temporal activity seen in Opt-blur.
Individual components of the near triad have been dissected in
paralysed anaesthetized cats using the microelectrode stimulation
technique. Accommodative/vergence processing in the cat is known
to occur within the lateral suprasylvian sulcus (LS) and middle
suprasylvian sulcus (MSS), both extrastriate parietotemporal regions
with homology to macaque V5 (Bando & Toda, 1991; Yoshizawa
et al., 1991). Furthermore, Jampel (1960) found ARs, in addition to
vergence eye movements and pupillary constriction, evoked by
electrical stimulation of the cerebral cortex surrounding the superior
temporal sulcus (STS) in the macaque temporal lobe.
The parietal rCBF decreases are interpreted, likewise, as a
disengagement of the cortical system responsible for covert and
overt visual search. Speci®cally, the left parietal lobule (BA 39/40)
was functionally coupled with rCBF decreases occurring within the
right FEF (BA 6) during the cortical processing of VPA. Ample
evidence suggests that the inferior parietal lobule (IPL) of primates
plays a role in visually guided saccadic eye movements (reviewed
recently in Petit & Haxby, 1999). Lesions to the IPL in humans often
produce de®cits in saccadic eye movements (Pierrot-Deseilligny
et al., 1995). In a parallel PET study (Richter et al., 1998), adjacent
BA 39 (and BA 6) coordinates were also deactivated during the
execution of monocular negative voluntary accommodation.
IPL and BA 39 posterior parietal neurons in the macaque are
known to carry premotor spatial signals relevant to changes in gaze
within three-dimensional space relative to the plane of ®xation
(Sakata et al., 1980; Gnadt & Mays, 1995). However, the present
VPA paradigm did not require any overt three-dimensional spatial
shifts in posturing of the ARs. The posterior parietal association
cortices are also critical for directed attention, visual-spatial analysis
and vigilance in the contralateral hemisphere (Mountcastle et al.,
1977).
Frontal deactivations during VPA
Cerebellar involvement in VPA
The frontal rCBF decreases are interpreted principally as a
disengagement of the systems specialized for visual search during
cortical processing of accommodation/vergence eye movements.
Multiple prefrontal cortical ®elds involve sensorimotor processing for
eye movements: frontal eye ®elds (FEF); supplementary motor area
(SMA); supplementary eye ®elds (SEF); and several adjacent
prefrontal regions (Mitz & Godschalk, 1989). Many of these regions
have been visualized during neuroimaging studies of oculomotor
tasks (Fox et al., 1985; Paus et al., 1993; Petit et al., 1993; Lang et al.,
1994; O'Driscoll et al., 1995; Petit & Haxby, 1999). Several of these
regions also activate during covert visual orienting of attention
(Corbetta et al., 1998; Gitelman et al., 1999). During VPA, the neural
systems involved in accommodative/vergence and visual search
appear partly dissociable; prefrontal systems participating in visual
search (e.g. orienting of visuospatial attention, voluntary saccades
and smooth pursuit) deactivate in the presence of synkinetic
accommodative/vergence movements in the occluded eye and small
amplitude eye movements in the ®xating eye. De®nitive dissection
will require simultaneous high-resolution recording of eye movements while scanning during VPA and visual search. In a parallel
Several activations localized to the vermis and cerebellar cortex. The
cerebellum is interconnected with many regions showing changes in
activity during VPA (Bando et al., 1984; Kawasaki et al., 1993). The
cerebellum receives a direct projection from the superior temporal
sulcus (or lateral suprasylvian area) via the pontine nuclei. Cerebellar
efferents project to the pretectum and parasympathetic oculomotor
neurons. Recent reports document monosynaptic connections between FEF, IPL and the dentate nucleus, as well as between the
dorsolateral prefrontal cortex (e.g. BA 46), globus pallidus, thalamus
and dentate (Lynch et al., 1994; Middleton & Strick, 1994).
The cerebellum is implicated in human accommodation. Kawasaki
et al. (1993) described a patient with a cerebellar lesion who
presented with `dif®culties at focusing on both near and far.' The
patient had signi®cantly increased accommodation and relaxation
times bilaterally. Gamlin & Clark (1995) studied in alert-behaving
rhesus monkeys the single unit activity in the nucleus reticularis
tegmenti, a precerebellar nucleus. Cells displayed bursts of activity
during far-to-near viewing. Many had a tonic ®ring rate which
increased as a function of increases in accommodation as well as
convergence. Interestingly, the cells were often in close proximity to
FIG. 8. Individual DrCBF decreases from VPA minus No-blur in right frontal
BA 6 coupled with simultaneous decreases in left parietal BA 39/40. The
Talairach co-ordinates (x, y, z) for these ROI are listed in Table 1b (regions 2
and 4).
Ó 2000 European Neuroscience Association, European Journal of Neuroscience, 12, 311±321
320 H. O. Richter et al.
neurons with saccade-related ®ring. The functional role of the vermal
activation in the present study may relate uniquely to the processing
of VPA (Ohtsuka & Sawa, 1997). The vermal area (lobule VII)
receives information from visually responsive neurons including
nucleus reticularis tegmenti (Schmahmann, 1996). Zhang & Gamlin
(1998) found in a detailed study single units in the cerebellar
interposed nucleus, connecting to the nucleus reticularis tegmenti,
activity related to vergence and accommodation irrespective of
whether or not these eye movements were elicited by blur or disparity
cues. Current PET techniques would be insensitive to the detection of
activity in such a small volume.
Conclusion
Our data show that VPA recruits circuits dissociable, in part, from
those participating in other oculomotor tasks. Many of the recruited
regions process visual information during ®xation steady-state
accommodation, as they are also active during both No-blur and
Opt-blur. The analysis of ROI in the visual cortex showed systematic
and appropriate task dependence on rCBF in the great majority of the
subjects. This gives credence to the validity of the present measures
and to the approach used here. These data identify an extensive
network of cortical and cerebellar regions involved in VPA. Overall,
VPA is associated with rCBF increases in posterior structures
(occipital, cerebellar and temporal regions), and with rCBF decreases
in frontal and parietal regions. Many of these structures were
previously implicated in re¯exive computations of accommodation
from lesion studies and electrophysiological experiments in monkeys
and cats (Maekawa & Ohtsuka, 1993). An interesting observation is
the dynamic and reciprocal functional connectivity during VPA
between the accommodation and visual search/visual attention
systems. The saccade and accommodation systems share premotor
circuitry based upon the direct connections between accommodation
units in the superior colliculus and omnipaus neurons in the saccade
system (Ohtsuka & Sato, 1996). However, functional linkage between
these oculomotor systems is only now emerging and has relied on
histological studies. The absence of activation in the anterior
attention system and the deactivation in regions supporting covert
orienting of visuospatial attention (and overt eye movements)
suggests that these networks are dissociable from those mediating
VPA.
Acknowledgements
We thank our study participants for their cooperation and patience; Dr Satoshi
Minoshima (University of Michigan) for providing software for PET data
analyses; Dr Michael Kuskowski for statistical consultation; Dr Richard Robb
(Mayo) for providing ANALYSETM software; Chris Fy and the Eye Clinic
(VAMC, Minneapolis, MN, USA) for performing optometric evaluations;
Priscilla Weber for editing; Dr Ying Han for eye movement recordings with
the Ober-2 Eye-Movement System; and two anonymous reviewers for their
important comments. This work was supported by the Department of Veterans
Affairs, USA, and the Karolinska Institute/University of Minnesota Exchange
Program. Dr Richter was a Postdoctoral Fellow supported in part by the
Fulbright Commission, the Swedish Institute, the Swedish Crown.
Abbreviations
AR, accommodative response; Dig-blur, digitally blurred checkerboard;
DrCBF, subtracted regional cerebral blood ¯ow; FEF, frontal eye ®eld;
FWHM, full-width at half-maximum; IPL, inferior parietal lobule; No-blur,
normal (0.0 D `blurred') checkerboard; Opt-blur, ±5.0-D blurring of checkerboard; PET, positron emission tomography; rCBF, regional cerebral blood
¯ow; ROI, region of interest; SEF, supplementary eye ®elds; SMA,
supplementary motor area; VPA, ±5.0-D blurring of checkerboard and VPA;
VPA, voluntary positive accommodation.
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