Abstract
Purpose:
We sought to characterize neural motion processing deficits in children with cerebral visual impairment (CVI) who have good visual acuity using an objective, quantifiable method (steady-state visual evoked potentials [SSVEPs]).
Methods:
We recorded SSVEPs in response to three types of visual motion – absolute motion and more complex relative and rotary motion, comparing them to form-related vernier and contour responses. We studied a group of 31 children with CVI diagnosed via detailed clinical examinations and 28 age-matched healthy controls.
Results:
Using measurements made at the appropriate response harmonics of the stimulation frequency, we found significant deficits in cerebral processing of relative and rotary motion but not of absolute motion in children with CVI compared with healthy controls. Vernier acuity, in keeping with good recognition acuity in both groups, was not different, nor were contour-related form responses.
Conclusions:
Deficits for complex motion but relative sparing of elementary motion and form-related signals suggests preferential damage to extra-striate visual motion areas in children with CVI. The fact that these preferential losses occur in the absence of significant acuity loss indicates that they are not secondary to reduced visual acuity, but rather are an independent vulnerability in CVI. These results corroborate parental and caregivers’ reports of difficulties with tasks that involve motion perception in children with CVI.
Cerebral visual impairment (CVI) is the leading cause of childhood visual impairment in developed countries. Because its prevalence is rising in developing countries, it is now a major public health concern.
1–3 CVI commonly results from disruption to retrochiasmatic visual pathways and visual processing regions of the brain occurring during gestation, at delivery, or shortly thereafter.
4 The most common causes are perinatal hypoxia, hydrocephalus, and structural brain abnormalities. CVI is often associated with prematurity and comorbid cerebral palsy with periventricular leukomalacia, the most common brain lesion.
5–9
CVI was previously diagnosed on the basis of reduced visual acuity alone in the presence of a normal ocular examination. This has limited the understanding of the condition. CVI has now been redefined as “A verifiable visual dysfunction, which cannot be attributed to disorders of the anterior visual pathways or any potentially co-occurring ocular impairment.” CVI encompasses a spectrum of visual and perceptual deficits collectively termed disorders of higher visual perceptual impairment or higher visual function deficits (HVFDs).
7,10–14 In essence, the diagnosis of CVI is now a clinical diagnosis based on assessment of risk factors, exclusion of a purely ocular cause of the visual function impairment, supplemented when possible by other investigations, such as brain magnetic resonance imaging (MRI) scans. Normal visual acuity and absence or presence of brain MRI findings does not exclude a diagnosis of CVI.
7,15
HVFDs may be the only symptomatology of children with good visual acuity in the presence of CVI.
16–19 In fact, a significant number of children with CVI who have good visual acuity remain undetected for higher visual function deficits, leading to significant difficulties in everyday life, school environments, and integration into society.
10 Higher visual functions (HVFs) are mediated by two putative cerebral networks; the “dorsal stream” connecting occipital and parietal lobes; and the ventral stream comprising occipital areas (e.g. V4) and temporal lobes.
20,21 HVFs, such as motion, dealing with complex visual scenes, navigation through three dimensional space and visually guided movements are assigned to the “where” or “action” dorsal stream, whereas color, shape, object, word, and face recognition are assigned to the “what” ventral stream.
22–24 Functionally, there is considerable integration between the two streams to execute most visual functions, such as identification of objects and visually guided motion to reach and grasp.
25 In early life, functional morphology of the brain representing the dorsal stream is thought more vulnerable
19 resulting in a preponderance of dorsal stream deficits of HVFD in conditions leading to CVI.
26
Alterations in motion perception are frequently observed by parents and teachers of children with CVI, as documented in structured history question inventories
27–31 and studied by psychophysical measurements that include biological form motion, optic flow fields (e.g. random dot kinematograms), and spatial integration tasks.
14,32–34 Most ambulant activities require accurate complex motion processing feeding onto the motor pathway for walking, reach and grasp, and avoidance of danger, such as avoiding traffic. The presence of these higher-order motion processing deficits suggests that specific testing for motion deficits using an objective method may yield high diagnostic value. Visual evoked potentials (VEPs) provide objective measures of brain function that promise to extend the possibility of a CVI diagnosis to earlier ages and nonverbal participants. Early work with VEPs has shown vernier acuity deficits,
35,36 spatial contrast sensitivity loss,
37 and translational and radial motion deficits.
38
To the best of our knowledge, only one study has utilized VEPs to measure motion-related responses in children with CVI.
39 Children in this study had low visual acuity and a CVI diagnosis based on periventricular leukomalacia (PVL) associated with prematurity or hydrocephalus. In this study, Weinstein and co-workers
39 showed selective global (but not local) motion deficits. However, children diagnosed with CVI with normal or near-normal visual acuity were excluded from the study, but controls had normal visual acuity, so deficits in motion processing could have been secondary to visual acuity loss.
Here, we use the steady-state visual evoked potential (SSVEP) to study both simple and complex motion processing in children who have normal or near-normal visual acuity with a clinical diagnosis of CVI, as defined by Sakki and co-workers,
11 comparing them to neurotypical children. By studying children with near normal visual acuity, we focus on deficits that are not likely to be secondary to reduced stimulus visibility. As an internal control, we measure responses to form-related aspects of two of our stimuli in order to focus specifically on motion processing alterations. We find preserved processing of simple motion and to formed responses, but reduced responses to more complex types of motion in CVI, suggesting that complex motion processing deficits – a form of akinetopsia – can occur independently of acuity loss in children with CVI.
Five GRASS 9 mm gold cup electrodes (model: E5GH) were placed according to the International 10–20 electrode placement system over the occipital pole at PO7, O1, Oz, O2, PO8, with the reference at Cz and ground at Pz.
54,55 Responses were recorded for each participant in a single session. A familiarization session was set up prior to proceeding with testing with the three stimulus conditions. Each stimulus condition consisted of six to ten 10 to 12 second trials and presentation order was randomized across conditions.
Most children sat on their own with their parents beside them; fixation was monitored constantly for all participants by the tester through a small cutout in a black screen that surrounded the monitor. Early in the course of the study, a remote video camera was introduced as an additional monitor for fixation for most (As the camera was introduced during the early part of the study, not all participants had this additional monitoring. However, the mainstay of the monitoring of fixation was based on direct observation through the cutout for all participants). of the participants. All stimuli were viewed binocularly with spectacle correction, if prescribed. Attention to the stimulus was actively encouraged by a central cross fixation target, additional small toys dangling around the center, age-appropriate rhymes, and stories or the child's own favorite audiotape. The presentation was stopped if the experimenter judged a participant to not be paying attention and restarted upon re-engagement. Rest periods were given at regular intervals throughout the session.
Each of the paradigms used in the present study involves measuring evoked-response amplitude as a function the value of the paradigm's swept parameter. Each paradigm can elicit evoked activity at one or more harmonics of each temporal frequency in the stimulus. Responses are not present at some harmonics, say, for example, odd harmonics of the absolute motion paradigm due to symmetry considerations. Responses at some harmonics can have low signal-to-noise ratio and thus are not reported. We thus focus the reporting on the harmonics that are expected from the design of the paradigm and of those that have adequate signal-to-noise ratio in all or some of the electrodes to be interpretable. Thresholds for the swept parameter are derived from these response functions as appropriate. In the figures, we display all five electrode responses if there are interpretable responses from the majority of electrodes.
Figure 2 shows the response amplitudes and significance criteria for the second harmonic response to the fast-jitter stimulus used to assess the integrity of responses to absolute motion (see
Appendix B for the fourth harmonic fast-jitter harmonic responses). Each subpanel within the figure corresponds to one of the five electrodes spanning from the left hemisphere (PO7-Cz) to the right hemisphere (PO8). Data for the typically developing children are shown in blue and the responses for the children with CVI are shown in red.
The absolute motion response measured at 15 Hz is largest at Oz where it increases monotonically as a function of displacement, falling off rapidly at lateral electrodes PO7 and PO8. The responses in the CVI group do not differ from those of the control group at any of the displacements measured (see lower panels - dotted line indicates P < 0.05 significance level).
Absolute motion thresholds from the individual participant data records are shown as histograms of best and second-best thresholds in
Figures 3A and 3B. Between the two groups there was no statistically significant difference for either the means of best (CVI group = 0.45 arcmin and the control group = 0.57 arcmin, t(35.2) = 1.16,
P = 0.25) or second best (0.65 arcmin for CVI versus 0.82 arcmin for controls: t(34.9) = 1.32,
P = 0.19) thresholds.
However, although thresholds for best and second best electrodes for neurotypical subjects were not significantly different (t(50) = −1.16, P = 0.1); children with CVI did show a significant difference for best and second best electrodes (t(54) = −2.82, P = 0.006).
This is the first prospective, controlled study to characterize motion processing deficits in children with an established clinical diagnosis of CVI and good visual acuity using a direct neural measure, the SSVEP. Our results show that children with CVI have deficits in even harmonic responses in the vernier and contour-in-noise paradigms, but not in the absolute motion paradigm. That these processing differences preferentially involve more complex forms of motion processing is borne out by our observation that form related first harmonic responses measured at the same time in the vernier and contour paradigms are relatively unaffected. In the case of the contour-in-noise paradigm, even harmonic responses to the contour elements themselves are affected, despite the odd-harmonic responses being not measurably different. Depression of the contour-related even harmonic responses may reflect preferential crowding of motion vs form processes when the density of the noise patches is high. Absolute motion, a simpler type of motion, is unaffected in our measurements.
It is likely that the even harmonic responses reflect – at least in part – the activity of motion rather than local contrast-change mechanisms. In the case of the absolute motion condition, this response is subject to direction-specific adaptation.
58 Moreover, this stimulus elicits the monocular developmental motion asymmetry in the VEP.
59 These past results suggest that even harmonic responses from this paradigm at least partially tap activity from direction-selective motion mechanisms in early visual cortex. In the future, it would be useful to rule out temporal frequency (e.g. 7.5 Hz versus 3 Hz) as the factor that spares the response to the oscillating grating compared to the other motion types.
Evidence for a motion contribution to the vernier second harmonic is less direct. The original publication on the vernier VEP paradigm used here
46 showed that both 1F and 2F thresholds were in the hyper-acuity range and that both had a steep eccentricity dependence typical of other hyperacuities. The fine thresholds and steep eccentricity dependence of the vernier 2F response suggest that it is not primarily a response to local contrast change which would be expected to be less dependent on eccentricity.
60
The involvement of direction-selective (motion) processes in the generation of even harmonics in the contour-in-noise paradigm is unknown, as this type of motion has not been studied neurophysiologically. Nonetheless, these even harmonic responses are preferentially affected in CVI. Analogous to the responses to the vernier stimulus, even harmonics from the contour elements are preferentially reduced in amplitude compared to the first harmonics from the same elements, consistent with a relative sparing of form processing in both paradigms.
Our results are consistent with prior results suggesting that CVI preferentially damages more complex motion processing mechanisms, while sparing simpler ones.
31,35,44 Importantly, we show that these losses occur in the relative absence of visual/vernier acuity and contour-integration deficits and are thus preferential to the motion pathway. Guzetta and co-workers
34 reported reduced behavioral responses to complex motion stimuli (segmented motion) in children with normal visual acuity born prematurely with PVL compared to a similar cohort of children without PVL lesions, indicating that higher-order motion perception is affected in children at higher risk of CVI (prematurity and PVL) independent of visual acuity. Our results provide electrophysiological evidence for the psychophysical deficits of motion abnormality in their cohort. Weinstein and co-workers
39 showed selective global (but not local) motion deficits in children diagnosed with CVI based on presence of PVL lesions associated with prematurity or hydrocephalus, children with CVI with normal visual acuity were excluded from their study, but controls had normal visual acuity, so deficits in motion processing could have been secondary to visual acuity loss. Taken together, our results are consistent with patterns of differential loss of higher-order motion perception in patients with preserved pre-striate and striate areas but damage to extrastriate dorsal stream areas.
19,61–63
Our objective results corroborate reports of a spectrum of perceptual motion processing difficulties documented with structured question inventories that have included questions aimed at assessing dorsal stream motion processing dysfunction.
4,30,31,64 An inability to see moving objects, such as cars on a road, while the child is stationary or an inability to spot animals in a field while the child is seated in a moving car are frequently reported, especially when the visual environment has multiple features. Dutton and co-workers
65 used structured questionnaire to study 40 children with clinical diagnosis of CVI due to multiple etiologies, similar to our study. In their group, 31 had 6/12 (20/40) or better binocular visual acuity; in 13 children, parents had observed impaired ability to see moving objects while stationary and all 40 had impaired visually guided motion. Our results demonstrating relative and rotary motion abnormalities are possibly related to these behavioral observations.
We also report that two form-related responses – the first harmonics of the vernier onset-offset and contour-alignment/misalignment responses (see
Figs. 6,
7,
9, respectively) are relatively undisturbed in our CVI group. The vernier-related response is not measurably different at small offsets and the derived vernier acuity does not differ between groups (see
Fig. 7). By contrast, responses at the second harmonic (2F) from the same stimulus are right-ward shifted and 2F thresholds are higher in the children with CVI, suggesting a relative sparing of form processing mechanisms. Vernier-related responses do, however, differ at large offsets, suggesting that any sparing of form processing is relative rather than absolute. VEP vernier acuity is correlated with logMAR acuity loss in amblyopia
66 and these points of concordance suggest that vernier acuity provides a surrogate for recognition acuity and thus may serve as a useful early predictor of recognition acuity in preverbal children unable to perform traditional behavioral recognition acuity. The first harmonic of the contour-related response does not differ between groups in our measurements, but even harmonic responses related to both the contour and noise elements do differ, again suggesting a relative sparing of form-related processes.
CVI diagnosis encompasses children in which CVI was likely caused by a range of different brain lesions that can be detected on neuro-imaging and a spectrum of functional deficits that are either directly or indirectly related to these structural abnormalities. Because of the nature of the diagnosis, there are comorbidities in our cohort of children that could influence the pattern of results.
11 For example, in our group, only 5 of 31 children had normal brain MRIs and only 7 of 31 did not have strabismus. The question is then which functional alterations are secondary to the comorbidities and which are in some sense “primary” to CVI. Our sample is too small to make a statement about the effects on the different VEP measures in a group of children without CVI who do not have strabismus or who did not have brain abnormalities on MRI. This question has at least partially been addressed in a study of coherent motion VEPs
39 where it was concluded that alterations of the VEP were more pronounced in children with CVI and strabismus than they were in otherwise healthy children with strabismus. Similarly, motion processing deficits, including a differential loss for higher levels of motion perception, including biological motion, have been reported in children born prematurely; with CVI
67,68 and without CVI
34,69,70 with the addition of CVI inducing greater loss. What we show here is a pattern of relative sparing and deficit over multiple functional measures in a high visual acuity CVI population.
In children with CVI, normal MRI scans in the presence of abnormal neurology and vice versa are seen in this and other studies. Limitations of resolution in routine clinical MRI scans suggest that absence of abnormalities
41,42 or indeed a normal MRI postdating an abnormal cranial ultrasound does not exclude CVI.
71 Increasingly, arguments are being made for inclusion of additional supportive evidence of CVI. These include macro and micro-level structural brain abnormalities, attention deficits, visual perceptual spatial processing deficits, and other learning disorders with or without visually guided motor deficits.
13,72,73 The possible influence of additional comorbidities in our population, such as autism, strabismus, and amblyopia, are mitigated by the consistency of diagnosis of CVI for the entire study cohort whereas the comorbid conditions are sporadic. Nonetheless, much remains to be done to tease out the spectrum of visual deficits in children with CVI and the influence of comorbid conditions.
74,75
The authors thank the children and parents who participated as volunteers in the study. We thank Sylwia Migas, PhD for help with collection of data; Devashish Singh, Research Assistant, for his input; Laurence Abernethy, Neuroradiologist, for information on brain imaging, and members of the eye department Alder Hey Children's Hospital, UK, for assisting in recruitment and support for the study. We gratefully acknowledge the hard work of Nikolay Nichiporuk, who passed away prior to the submission of this paper.
Supported by ongoing grants for CVI research from vision4children (The Littler Trust) UK; Iceland Foods Charitable Foundation (UK), a SKERI grant to A.C. (USA), and a RERC grant (90RE5024-01-00; USA).
Disclosure: A. Chandna, None; N. Nichiporuk, None; S. Nicholas, None; R. Kumar, None; A.M. Norcia, None
Appendix A: Tables 1A and 1B. Clinical Data for Patients in This Study