VERP and brain imaging for identifying levels of visual dorsal and ventral stream function in typical and preterm infants

O. Braddick, J. Atkinson and G. Innocenti (Eds.) Progress in Brain Research, Vol. 189 ISSN: 0079-6123 Copyright Ó 2011 Elsevier B.V. All rights reserved.

CHAPTER 6

VERP and brain imaging for identifying levels of visual dorsal and ventral stream function in typical and preterm infants Oliver Braddick{,*, Janette Atkinson{ and John Wattam-Bell{ {

{

Department of Experimental Psychology, University of Oxford, Oxford, UK Visual Development Unit, Department of Developmental Science, University College London, London, UK

Abstract: Visual development is a key area for understanding and assessing early brain development. Different levels in the hierarchy of visual processing, from the initial response to flashes of light, through selective responses to contour orientation and motion in primary visual cortex (V1), to global processing in extrastriate of large-scale patterns of form and motion, can each be assessed using stimuli designed to isolate specific neural activity in visual event-related potentials (VERPs). This approach has been used to reveal the sequence of emergence of different visual cortical functions in the first 6 months of typical human development, and to provide early indicators of anomalies in brain development. Delayed or absent onset of orientation-reversal (OR-)VERPs, as a measure of cortical development, has been shown to be a sensitive indicator of perinatal brain damage in both term-born and prematurely born infants. Direction-reversal (DR-)VERPs appear a few weeks later than OR-VERPs in typical development, and are further delayed in even healthy children born preterm, reflecting possible early vulnerability of the motion (dorsal stream) system. High-density recordings of responses to global motion and global form patterns show that these extrastriate systems are typically functional by 5 months of age, but the topography of the activity distributions shows that the brain systems underlying these responses are radically reorganized between infancy and adulthood. In prematurely born infants whose structural brain MRI was evaluated at birth, the onset of the response is absent or delayed in those with severe brain injury, while in those with mild/moderate brain injury the response is present but its spatial organization is further from the adult pattern than those in controls.

*Corresponding author. Tel.: þ44-1865-271355; Fax: þ44-1865-271356 Email: [email protected] DOI: 10.1016/B978-0-444-53884-0.00020-8

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These findings are related to the development of distinct networks of brain areas in the dorsal and ventral cortical streams, and the apparent vulnerability of the dorsal-stream network in a wide range of both genetic and acquired developmental disorders. Keywords: visual development; evoked potentials; cortical development; global visual processing; perinatal brain injury; dorsal stream vulnerability.

Introduction

The visual processing hierarchy

Visual development is a key area for understanding and assessing early brain development for several reasons. First, vision provides the main sensory channel that gives the developing child information about the world of objects and space beyond their body surface, and also provides a vital base for the child’s developing understanding of their social world. Second, through a long history of psychophysical and neuroscience research, both on humans and on other species, we have a deeper and more detailed understanding of the brain mechanisms underpinning vision than for any other area of cognitive processing. Thirdly, the fact that some aspects of vision develop early in infancy, and that we have techniques for investigating them, means that vision can act as a window into the developing brain more generally. The approach we describe in this chapter has taught us much of what we know about how the functions of human visual cortex emerge in the first year of life. It has also provided ways to identify anomalies of brain development at stages when motor or communicative behavior is too immature to be diagnostic. It can help predict neurocognitive outcome in the early stages of developmental disorders arising, for example, perinatal brain damage, and so has the potential to provide an “early surrogate outcome measure” for evaluating new therapies and rehabilitation (see Atkinson and Braddick, 2007).

The visual system is commonly considered as a hierarchy of processing stages. This hierarchy begins with the photoreceptors, each of which transduces and signals the light intensity in a very small local region of the field of view. It appears to be a quite general finding of single-neuron recordings that receptive field sizes increase progressively at successive stages of the visual pathway (Maunsell and Newsome, 1987). Each subsequent level integrates information from the level below, allowing neurons to respond to information over progressively more extended regions (larger receptive fields) and to encode more complex properties of the visual image. If we can devise methods to isolate the sensitivity to higher level, more complex visual properties from lower level, more local properties, we can investigate the typical and abnormal development of the different stages of the hierarchy. In taking this approach, we need to recognize that the hierarchical model is incomplete in at least two important ways. First, the visual pathway shows parallel as well as serial differentiation of function. That is, at both precortical and cortical levels, there are parallel pathways which show a different balance in the way they respond to properties of the visual world. Here, we will be particularly concerned with the division between the “dorsal” and “ventral” streams of cortical processing (Livingstone and Hubel, 1988; Ungerleider and Mishkin, 1982). Both originate with information from primary visual

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cortex (V1), fed into different networks. The dorsal stream, which includes the motion-sensitive cortical areas V5 (MT) and V3/V3A and V6, transforms visual information into the form required by parietal and frontal lobe systems for the visual control of spatially directed actions (Milner and Goodale, 1995, 2008). The ventral stream consists of a distinct set of areas, including V4, the lateral occipital complex (LOC), and inferotemporal areas, and its functional specialization is for extracting pattern properties used for the recognition of objects and faces. Analysis of neural connectivity confirms that the majority of interconnections are between areas within a given stream (Felleman and van Essen, 1991; Young, 1992), although cross-connections between the streams must undoubtedly play an important role in the integration of visual behavior. Second, the hierarchical model must be modified to take account of the rich network of feedback connections through which “higher” cortical areas, in both streams, modulate the activity of “lower” areas, including V1 (Felleman and van Essen, 1991). The ubiquitous existence of these feedback connections means that, although selective responses that require the integration of spatially extended information must originate in computations performed by neurons with large receptive fields, and these are found at a relatively high level of the pathway, the responses we observe may well arise from feedback to a lower level such as V1. Further, developmental changes are likely to reflect the development of this feedback as well as the development of the high-level integrative computations.

Visual event-related potentials Visual event-related potentials (VERPs), also known as visual-evoked potentials (VEP), are electrical voltages recorded from the surface of the scalp that reflect neural activity in response to visual stimulation. Because these signals can be recorded from infants and children who are too young or too disabled to communicate their

perception of a visual event, they have provided one of the primary tools for investigating the development of the visual brain, both in typical development and developmental disorders (Atkinson and Braddick, 1999; Regan, 1989). This activity can be identified, within the much greater background noise, because it is timelocked to a repetitive visual stimulus event. Digital signal averaging of a series of “sweeps” each initiated in time with the event allows the visual signal to build up in the average much more than the background noise whose timing is unrelated to the stimulus. In a very simple case, the stimulus events could be flashes of light. These strongly activate the photoreceptors of the eye, but since the visual pathway beyond the photoreceptors primarily signals the contrast between different parts of the visual image, they have little significance for visual function in the cortex. One of the most widely used types of VERP testing is “pattern-reversal.” In a pattern of black and white stripes or checks, the black areas periodically turn white simultaneously with the white areas turning black. Since the average light intensity across the screen is not changed by this, the resulting VERP signal is a response to contrast rather than to light intensity per se. It can be recorded in infants at birth or even a few weeks preterm (McCulloch et al., 1999). Since it is recorded over the occipital region, it is generally presumed that the pattern-reversal response represents activity in or around V1. However, it is important to recognize that the VERP is unlikely to represent the effect of nerve impulses, but is more likely to arise from local field potentials associated with synapses (Wood and Allison, 1981). Thus, the presence of such VERPs in young infants indicates that neural information about visual contrast must be reaching the input to the cortex (excitatory synapses in layer 4 of area V1), but tells us little about the maturity of processing that goes on within the developing visual cortex. It may still be informative about the course of neural and cerebral development. Specifically, the latency of this pattern-reversal response is a

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developmentally sensitive indicator; in typically developing infants, it falls by about 150 ms from birth to reach adult values around 100 ms about 4–5 months of age (McCulloch et al., 1999; Porciatti, 1984). It can therefore be used as an indicator of the integrity of the input signal to the cortex. For example, in a current ongoing collaborative study, we are using this latency measure to gauge the extent of recovery in infants with perinatal brain damage at risk of cerebral palsy, and the effectiveness of a dietary intervention. The latency changes may reflect myelination of the optic tract and radiation (Friede and Hu, 1967; Dubois et al., 2008), and thus possibly, the broader development of cerebral white matter; the initial cortical response to incoming sensory information may also contribute. In attempting to relate ERPs to specific anatomical sites in the cortex, it is important to realize that the relation between topography of responses on the scalp, and the location within brain tissue of the neural events that generate them, is complex. Given as a source an electrical dipole of known location in the head, the scalp voltages can be calculated if we have a good “head model” incorporating the anatomical form and electrical properties of brain tissues, bone, cerebrospinal fluid, etc., preferably based on individual magnetic resonance images (MRIs) of these structures. The “inverse problem” of inferring the source(s) from the scalp voltages can only be solved with problematic assumptions (e.g., that a single dipole is a good model) (Scherg, 1990). But in any case, the head model for infants is much more speculative than it is for adults, and it is rarely possible to base it on individual structural MRI. The approach we discuss here, therefore, is not primarily based on identifying sources anatomically, but on designing ways that can isolate responses arising from specific functional operations, which we believe from other evidence to be associated with particular levels of processing, and particular neural networks, in the visual hierarchy.

Selectivity of visual cortical neurons Evidence from single-neuron recording in area V1 of cat and monkey has revealed some of the operations performed by these neurons. Information has come to V1 from the retina via the lateral geniculate nucleus (lgn) of the thalamus and the computations by V1 neurons transform this information (Hubel and Wiesel, 1977). V1 neurons are highly selective for the types of stimulus which can activate them, compared to the neurons in the lgn providing their input which are in most respects unselective. Thus most of them are orientation-selective—they are only activated by a contour at a particular angle in their receptive field— and many are direction selective, responding to one direction of movement but not to the opposite. Neither of these types of selectivity is seen in neurons in the pathway from retina to cortex. Similarly, signals from the two eyes are brought together for the first time in area V1, and neurons are found here that respond selectively to binocular relationships, activated when the two eyes’ images match with a particular disparity. In looking at typical and atypical cortical development, therefore, we have used VERP stimuli which manipulate the properties for which these neurons are selective. However, care is needed to separate these selective responses from unselective responses to contrast change. We achieve this by using “steady-state” recording (Regan, 1989) in which the electrical response is analyzed to extract component frequencies which match the rate at which particular events occur in the sequence of visual stimuli. Figure 1 illustrates how orientationselective responses are isolated in this way. If we simply alternated gratings of two orientations (e.g.. 45 and 135 ), then many locations in the image would change from white to black or vice versa, giving strong contrast changes at the reversal frequency which could activate neurons with no orientation selectivity, such as those providing the cortical input. However, if we embed the orientation reversals in a series of random “phase jitters,”

99 Jitter every 40 ms (a)

Orientation reversals every 120 ms (b)

(c)

(d)

Fig. 1. Orientation-reversal VERPs. The grating stimulus (a) undergoes random phase-shifts (“jitters”) every 40 ms (25 Hz), and switches orientation every 120 ms (8.3 Hz). The ERP (b) contains response to both of these events, but they can be separated by Fourier analysis into a 25 Hz jitter component (c), and an 8.3 Hz orientation-specific component (d) (Braddick et al., 1986).

Jumps every 120 ms

Direction reversals every 240 ms Fig. 2. Stimulus sequence for direction-reversal VERPs. A random-dot pattern moves horizontally, reversing its direction of motion in the case shown every 240 ms (4.16 Hz). These reversals are accompanied by replacement of the dots with a new random array (a “jump”). “Jumps” also occur midway between direction reversals, every 120 ms (8.3 Hz). Thus, in a similar way to the orientation-reversal analysis in Fig. 1, neural activity associated with the contrast transitions at the jumps occurs at the frequency of 8.3 Hz, and the response of direction-selective mechanisms is isolated by analyzing the frequency component at 4.16 Hz.

these jitters, along with the orientation changes, produces a series of contrast changes at the jitter frequency, a multiple of the reversal frequency. In terms of local contrast changes, the orientation reversals are statistically indistinguishable from the jitter events. In this sequence, any VERP response at the lower, orientation reversal, frequency can only arise from neurons that respond specifically to orientation. Testing for this orientation-reversal (OR-) VERP in young infants has shown that the orientation-specific response is not present at birth, but emerges typically between 3 and 8 weeks of age, depending on the frequency used (Braddick, 1993; Braddick et al., 1986). A similar approach can be taken to directional motion selectivity, using the sequence shown in Fig. 2 where a random-dot pattern repetitively reverses its direction of motion. Again, by interleaving the reversals with “jumps” in which the random-dot pattern is replaced, nondirectional effects associated with the reversal can be controlled for, and the direction-reversal (DR-) VERP analyzed at the reversal frequency is a test for the activity of directionselective cortical neurons. This response has also been shown to emerge postnatally (Wattam-Bell, 1991) but later than orientation selectivity, a developmental sequence that has been confirmed by parallel tests on the same infants with OR- and DR-sequences (Braddick et al., 2005). The development of binocular interaction can be assessed by an analogous approach, using a display of dynamic random dots which alternate between binocular correlation and anticorrelation (Braddick et al., 1980, 1983; Julesz et al., 1980). These results can be summarized as shown schematically in Fig. 3 (Atkinson, 2000). At birth, the V1 is highly immature: its responses do not show any of the selective properties resulting from specifically cortical neural computations. These typically emerge in the first 3–4 months. However, the cortex is not uniformly “turned on” at a particular stage of development; instead its properties appear in sequence. All these properties must reflect the establishment of specific patterns of synaptic

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Development of early visual cortical selectivity Age

Orientation

Directional motion

0

5

10

15

Weeks post-term

Crude Temporal resolution discrimination improves at birth Temporal and spatial Specific VERP resolution improve first at 3 wk Behavioural discrimination first at 7 wk Specific VERP first at 10 wk

Binocular correlation and disparity

Velocity range expands Velocity range expands

Behavioural discrimination first at 11-13 wks specific VERP first at 11-13 wks

Disparity range extends

Fig. 3. Early course of specific selective functions of primary visual cortex (V1) in typical development (from Atkinson, 2000).

connectivity which provide the input to cortical neurons, and indeed the period from 2 months onward is a period in which V1 synapses are established at an astonishing rate (Huttenlocher and de Courten, 1987; Huttenlocher et al., 1982). However, the development of each form of selectivity does not simply await a general burst of synapse formation, but must depend on particular rules of development, input and plasticity which are specific to the synaptic organization underlying each form of selectivity. Table 1 summarizes the various forms of VERP testing discussed here, and the levels of visual processing which they can tap.

Global cortical responses V1 represents only the first stage of cortical visual processing. The further transformations required to enable the range of visual behavior are performed in a complex set of extrastriate visual areas (Felleman and van Essen, 1991; Maunsell and Newsome, 1987; Zeki, 1993), with distinct

networks of these areas forming the dorsal and ventral cortical streams. A key characteristic of these extrastriate visual areas is their sensitivity to the “global” organization of the visual input, that is, larger scale structures, which is achieved by direct or indirect integration of local, low-level information provided by area V1. Neurons in V1 have small receptive fields that respond to the low-level, local, features in the visual input discussed in the previous section. Extrastriate areas combine this local information in a variety of ways. A well-studied example is the area known as MT orV5, which integrates local directional responses coming from V1 to signal the common motion of groups of stimulus features (Britten et al., 1992; Mikami et al., 1986; Movshon et al., 1986). Sensitivity to motion coherence is commonly used to probe this integration: the coherent global motion of a dot pattern (e.g., rotation, illustrated in Fig. 4) is disrupted by making a proportion of the dots move incoherently, in random directions, rather than in the directions defined by the global motion structure. Down to some “coherence threshold,” subjects

101 Table 1. Visual event-related potentials to different stimulus events Stimulus

Process indicated

Age of onset

Flash Pattern reversal

Preterm Late preterm/term

Orientation-reversal (OR-VERP)

Light response—subcortical Spatial contrast response—input to cortex—not necessarily cortical processing Basic cortical pattern processing

Direction-reversal (DR-VERP) Binocular correlogram Onset/offset of global form and motion

Basic cortical motion processing Functional interaction of signals from the two eyes in cortex Higher level integration—extrastriate cortical mechanisms

Fig. 4. Stimulus for coherent rotary motion (direction of motion indicated by gray arrows; moving region indicated by gray dotted circle). The coherently moving region can be detected in the display of the right hand panel, compared to the incoherent motion (same dot trajectories, spatially scrambled) in the left hand panel.

can still detect the presence of the global coherent motion. Evidence that MT/V5 is involved in this function comes from the fact that it is impaired by MT/V5 lesions (Newsome and Paré, 1988), that the firing rate of individual MT/V5 neurons increases linearly with motion coherence (Britten et al., 1993), and their sensitivity is comparable to the behavioral sensitivity measured by motion coherence thresholds (Britten et al., 1992).

1–3 months (frequency dependent) 2–3 months 3–5 months Later than 2 months, motion before form

In addition to MT/V5, a number of other extrastriate areas respond to global motion, including V3a (Braddick et al., 2000; Sunaert et al., 1999) and V6 (Pitzalis et al., 2010). These areas are part of the dorsal visual stream; the prominence of global motion responses in this stream suggests that motion coherence sensitivity can provide an effective measure of its function and development. An analogous measure for the ventral stream exploits the fact that many ventral stream areas show selective responses to static global patterns—for example, area V4 contains neurons selective for circular and radial patterns (Gallant et al., 1993), which is presumably a result of integration of local orientation signals from V1. Sensitivity to global form coherence can be assessed with static patterns made up of short line segments arranged so as to define a global shape. Coherence can be varied by randomizing the orientations of a proportion of the line segments, as illustrated in Fig. 5. Functional MRI has been used to show the brain areas which respond to the difference between globally coherent and incoherent stimuli, in both the form and motion domains (Braddick et al., 2000; Rees et al., 2000; Wilkinson et al., 2000). These measurements confirm that responses to this difference occur in extrastriate, but not striate cortical areas, and that the extrastriate areas responding to global form and global motion are independent and nonoverlapping. However, the division between these independent

102 1 stimulus cycle (0.5 s)

f2: equal response to onset and offset; local

Fig. 5. Stimulus for coherent concentric form. The region of concentrically aligned arc segments can be detected in the display of the right hand panel, compared to the incoherent structure (same arc segments, spatially scrambled) in the left hand panel.

areas does not neatly follow the broad anatomical dorsal/ventral divide: foci of activity related to form coherence and motion coherence are both found in occipito-temporal and occipito-parietal areas (Braddick et al., 2000). Steady-state ERPs specific to global form and motion can be recorded with stimuli that switch periodically between 0% and 100% coherence (Fig. 6). Visual mechanisms that are sensitive to the global organization will respond to the onset and offset of coherence. These transitions also involve changes of the local orientation or motion direction, so a response at the frequency of alternations cannot distinguish between local and global responses. However, the local changes that occur at the onset and offset of coherence are statistically indistinguishable, and will on average generate equal responses. Onset and offset will only be distinctive for mechanisms that are genuinely sensitive to global structure. Thus, a VERP component at the lower frequency (the repetition rate of onsets, half the frequency of alternation) must arise from global processing, and separating these two frequencies allows global responses to be isolated from purely local responses (Braddick and Atkinson, 2007; Wattam-Bell et al., 2010) (Fig. 6).

f1: differential response to onset and offset; global Fig. 6. (a) The global form ERP stimulus alternates between 100% coherence, in which the short arcs are all aligned in a global concentric pattern, and 0% coherence, in which the arcs are randomly oriented. Each phase lasts for 250 ms. (b) Schematic illustration of local responses to orientation or contrast changes at each stimulus transition. On average, these will be the same for coherence onset and offset transitions, producing an ERP component at the frequency of these transitions (4 Hz). (c) Schematic of global responses in mechanisms differentially activated by coherence onset and offset. This global response—and thus the corresponding ERP component—has a characteristic frequency equal to the full onset–offset stimulus cycle, which is 2 Hz. Although this figure shows the form stimulus, it can also be taken as an illustration of the motion stimulus, with the static arcs representing the trajectories traced out by the dots over time.

These differential responses will be reflected in the ERP component at the frequency of the full incoherent–coherent stimulus cycle. The ERP will also contain responses to the local changes in direction or orientation that accompany the transitions between coherence levels. Tests of infants with these stimuli indicate that global form responses emerge at about 5 months of age. This is several weeks later that the onset of local orientation responses discussed earlier, which suggest there is an orderly local-to-global developmental sequence in the ventral stream. The development of global motion responses is quite different: we find them to be present at

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about 2–3 months, emerging close to, or possibly even simultaneously with, the onset of directionspecific responses (see above). These results indicate that the dorsal and ventral streams follow independent developmental trajectories in early infancy, as they do in later childhood (Gunn et al., 2002). They also imply an early maturation of extrastriate motion areas in the dorsal stream, a point that will discussed further below.

Multichannel ERPs We know from fMRI in adults that both form and motion coherence activate nonoverlapping networks of multiple extrastriate areas. While single-channel ERPs have provided valuable insight into the different developmental trajectories of the form and motion networks, they cannot tell us about differential development within each network: for example, do the various motion areas in the dorsal stream develop together or in sequence? To answer this kind of question, we need a way to distinguish the cortical origins of the different ERPs. This can be achieved with high-density recording, using an array of multiple (e.g., 128) EEG electrodes spaced evenly across the scalp, which provides information about the spatial distribution of the ERP. The spatial distribution depends on the geometry of the underlying brain sources generating the ERP; different distributions imply different sources, though the converse is not necessarily true. Hence, a comparison of the scalp distributions of ERPs to two different stimuli can indicate whether or not they are generated by the same cortical areas. Figure 7 shows the scalp distribution of global form and motion responses in adults and 5 month olds (Wattam-Bell et al., 2010). Both age groups show posterior response foci to form and motion, consistent with activation of visual cortical areas, and in both groups the form and motion responses have distinct topographies. In adults, the global motion response occurs close to the midline, whereas the global form response is

Form

Motion

40 Adults 20 0

30 Infants

20 10 0

Fig. 7. Scalp topography of adult (top) and infant (bottom) global form (left) and motion (right) VERP responses. This figure shows a view of the group statistical maps (darkness of the shading represents increasing values of Tcirc2, a statistic defining the reliability of the steady-state VERP signal at that location) over posterior electrode positions as viewed from behind the head; the dots represent individual electrode positions (Wattam-Bell et al., 2010).

more lateral. Infants show the opposite pattern: a midline form response and a more laterally located motion response. These results support the idea that global form and motion responses have distinct cortical sources in both adults and infants. More surprisingly, they also indicate that for both form and motion, the cortical sources have a different relationship between infants and adults, implying a developmental reorganization of the extrastriate networks underlying global processing. The lateralized motion response in infants is compatible with activation of MT/V5. The midline focus in the adult motion ERP, on the other hand, suggests that more medially located motion areas, such as V3a and V6, are dominating the responses. Thus, one possible interpretation of these results is that V5/MT is functional early in life, while other extrastriate motion areas come online later in development. This is supported

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by the finding that in nonhuman primates, anatomically V5/MT is the earliest maturing extrastriate visual area (Bourne and Rosa, 2006). However, the focus of the adult motion ERP lies immediately over the occipital pole, strongly suggesting a source in area V1. A number of adult fMRI studies have found that V1 is deactivated by coherent motion (relative to incoherent motion), and it has been suggested that this is a result of feedback, via recurrent connections, from extrastriate global motion areas. Consistent with this, we find that transient global motion ERPs in adults show both lateral and midline foci with opposite polarities, compatible with activation of V5 and deactivation of V1 by coherent motion. Moreover, the midline response is delayed relative to the lateral response, which is consistent with a suppression of V1 activity by feedback from V5. Thus, in addition to the early maturation of area V5/MT, the developmental change in global motion ERPs might also reflect relatively late maturation of recurrent projections from V5 (and, perhaps, other extrastriate areas) to V1. The functional changes underlying the development of the global form ERP require further exploration, but clearly a change in the balance of the contributing areas, and/or their network of interconnection, takes place in this system also.

VERPs as indicators of early atypical development The VERP methods described above have proved to be sensitive and revealing measures of brain function in children at risk of neurological problems, especially following perinatal brain insults with both prematurely born and term-born infants.

Term-born children with perinatal brain damage In a series of longitudinal studies on term infants with focal cerebral lesions or hypoxic-ischaemic encephalopathy (HIE), identified on neonatal

serial MRI brain imaging and neurological examination, we found that generalized lesions in HIE, involving a number of areas of the cortex, were associated with abnormal development of the OR-VERP, along with other measures of cortical visual function (Mercuri et al., 1996, 1997a). However, poor visual outcome is not necessarily most strongly associated with specific damage to classically “visual” areas of the brain. In particular, lesions seen on MRI in the basal ganglia, even without cortical damage, were generally associated with a more severe visual outcome than isolated cortical lesions (Mercuri et al., 1997b). This finding suggested that certain circuits between subcortical and cortical areas are essential for normal visual development, with little plasticity, while the cortical areas themselves involved in vision may show considerable plasticity in the face of damage. However, the extent to which basal ganglia damage may be associated with damage to other structures, less visible on MRI, needs to be further investigated. In 46 full-term infants with brain lesions visible on MRI, we found that 50% of our cohort did not show a significant cortical OR-VERP at 5 months of age (Mercuri et al., 1998). Fourteen percent of the cohort showed continuing delayed onset of cortical function using this indicator between 6 and 12 months of age, and in 34% the VERP responses remained nonsignificant. Infants with focal infarction or hemorrhage on MRI tended to show normal or only mildly delayed cortical responses, while Grade 2 or 3 HIE tended to be associated with persistent abnormalities of VERP responses. These measures also had predictive value. 96% of those who had shown 8 Hz ORVERP by 5 months were neurologically normal at 3 years, compared with 57% of those who attained the response by 12 months and 0% of those in whom it was still absent at 18 months (Mercuri et al., 1998). OR-VERP testing of 29 infants with HIE gave consistent prediction of Griffiths Developmental Quotient < 80 at 2 years (sensitivity ¼ 100, specificity ¼ 79, PPV ¼ 63, NPV ¼ 100) (Mercuri et al., 1999). In contrast,

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pattern-reversal VERP proved considerably less sensitive; children who showed this response in early infancy might nonetheless have a poor developmental outcome (Mercuri et al., 1998). This comparison suggests that the response which actually taps cortical processing (OR-VERP) is a better indicator of functionally significant impairment than the lower level which reflects the existence of a cortical response to input (pattern-reversal-VERP).

Early development of cortical selectivity in healthy preterms In an early study (Atkinson et al., 2002), we tested a group of infants at 1–3 months post–term age, who had been born at 24–32 weeks gestation. Those infants who had no neurological abnormality detected on ultrasound examination showed no significant difference on the onset of the ORVERP, compared to a term-born group matched for gestational age. Thus, preterm birth in the absence of neurological damage does not appear to either delay or accelerate these aspects of early cortical development. However, when the children in this group were included who showed minor or major ultrasound abnormalities (about 45%), OR-VERP was significantly delayed in the group taken as a whole, and the most severe cases of periventricular leukomalacia never developed the OR-VERP response during the first 4–5 months. These severe cases were associated with long-term neurological problems, including severe cortical visual impairment in one case. Although the study cited found normal ORVERP development in healthy preterms, more recently we have found that the development of cortical function is not uniform. Birtles et al. (2007), in a collaboration with neonatalogists at the John Radcliffe Hospital, Oxford, made parallel measurements at post–term ages between 6 and 20 weeks, of the OR-VERP and DR-VERP in a group of neurologically healthy children born preterm. Across this age range the OR-VERP

showed little change, and results from preterms and term-born controls were very similar. However, the DR-VERP is still developing, and the preterms showed several weeks’ delay in this development. Thus the direction-reversal response seems a more delicate indicator of the impact of prematurity than does the orientationreversal response, possibly because white matter damage that is not visible on conventional ultrasound (Dyet et al., 2006) may have a greater impact on motion processing, given that motion requires precise neural timing which may be disrupted if myelination is disordered. As motion processing is a feature of the dorsal stream while orientation is an elementary property required by the ventral shape-recognition system, this differential impact of prematurity on the two processes can be considered as an early example of “dorsal vulnerability” (discussed below).

Cortical measures in the first year related to MRI findings in preterms A subsequent collaborative study between the VDU group and the Hammersmith Hospital team provided the opportunity to assess cortical visual function between 2 and 7 months in infants born before 33 weeks gestation, for whom structural brain MRI results taken at term were available. These MRI results were classified on a 3-point scale of severity which took white matter abnormality assessed by the presence of DEHSI (diffuse excessive high-signal intensity), as well as the presence of frank lesions (Atkinson et al., 2008a). The OR-VERP test (and also the fixation shift test, a behavioral measure reflecting cortical development) showed that the proportion of these infants reaching a “passing” criterion for their postterm age progressively decreased with increasingly severe MRI findings. Further, the OR-VERP results, and the fixation shift results, predicted the infants who would show a developmental quotient < 80 on the 2-year Griffiths assessment, with sensitivity 86% and 100%,

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respectively, and specificity 61% and 65%. Thus, these cortical visual measures are associated both with imaging indicators of the condition of the brain at term, and with overall neurocognitive development in subsequent years.

Global visual processing in atypical development As outlined above, by using stimulus sequences which alternate between a globally coherent and random structure, defined either in static form or in motion, it is possible to isolate a VERP response which depends on the brain’s ability to extract these global structures. Having demonstrated that by 5 months, infants can show

responses of both kinds, we have started to use these tools to examine the effect of prematurity on development of these higher visual processing functions, in collaboration again with the Hammersmith group. In this new cohort, MRI results have been categorized according to a more refined system, summarized in Table 2. The use of a high-density EEG sensor array makes it possible to ask two kinds of question: first, can we record specific responses as evidence of global processing, and second, does the anatomical distribution of these signals differ in infants born preterm from term-born controls? (Atkinson et al., 2008b). Figure 8 shows data on the first of these questions, indicating the relative strength of

Table 2. Outline of the scoring system used for term MRI results in the study of global form and motion processing in 22 infants born <33 weeks gestation 

Neonatal MRI damage scored 0–20 (white matter damage, cysts/lesions, basal ganglia/thalamus damage, cerebellar damage) “Visual network” scored 0–10 (optic radiation, thalami, occipital cortex, dorsal and ventral cortical streams)  “Mild/moderate”: total score < 6, visual network ¼ 0 (N ¼ 12) “severe”: total score ¼ 6–14, visual network ¼ 1–7 (N ¼ 10) 

Scoring of MRI images was performed by Prof. Mary Rutherford.

5 Controls

Signal:noise ratio

4

Mild/moderate Severe

3

2

1

0 Pattern reversal

Global motion

Global form

VERP stimulus Fig. 8. Maximum signal:noise ratio in steady-state VERP recordings for pattern-reversal, global motion, and global form stimuli, in prematurely born infants with mild/moderate versus severe MRI findings at term (see Table 2), compared with term-born controls. All infants were tested between 4 and 5 months postterm.

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VERP responses in preterm-born infants in different MRI categories, and term-born controls, for the simple pattern-reversal response and the global responses to motion structure (coherent rotation) and global form (concentric organization). The pattern-reversal response appears unimpaired in the preterm groups, as does the global form response (although in many infants of all groups, this global form response is only starting to emerge by 5 months of age). The most striking differences are in the global motion response, which is strong in the controls and those with normal/mild MRI findings, but markedly weaker in the group categorized as “severe.” The greatest impact of damage is on the dorsalstream function, a recurring theme. Children with mild or moderate MRI findings following very preterm birth may show a similar signal strength to controls, but this does not mean that their underlying global motion processing mechanisms are the same. Typically developing infants showed significant reorganization of the pattern of activation across the scalp between 5 month olds and adults (Wattam-Bell et al., 2010), as discussed above. In particular, the response to global motion, which is strongest on the occipital midline in the adult, showed markedly more lateral foci in infant participants. Figure 9 shows that the pattern of response in children with mild or moderate MRI findings is markedly different from controls of the same post-term age. Specifically, the lateralized foci which occur in the control infants appear even more prominent, and more lateral in these prematurely born infants. This may represent a more immature configuration in the transition from the infant to adult pattern—a hypothesis which may be tested when data from younger control infants is available As we have noted earlier, it is not straightforward to infer the anatomy of the underlying neural sources from data such as that shown in Figs. 7 and 9; ideally, this would require individual structural MRIs at the same age as the recording, and data on the electrical properties of infant cranial

Controls

Prems ⎯ “mild/ moderate group”

Difference

Fig. 9. Scalp distribution of VERP responses to global motion, in the preterm born group with “mild/moderate” MRI findings (centre) compared with the term-born controls (left). Dots show sensor locations on a flattened representation of the head. The inner circle represents the circumference of the head at its widest point; positions outside this circle are scalp positions outside this line, for example, below the inion in the occipital region. The darkness of the shading represents increasing values of Tcirc2, a statistic defining the reliability of the steady-state VERP signal at that location (see WattamBell et al., 2010).

tissues to model the process by which intracerebral currents generate voltages at the scalp. However, it is tempting to suggest that the isolated lateral foci seen in the centre panel of Fig. 9 represent isolated activity of the motion-sensitive area MT/V5, without the complex network of connected brain areas seen in response to motion coherence in the adult brain (Braddick et al., 2000). We are currently exploring the hypothesis that the development of global motion responses during infancy and childhood reflects an increasing role of feedback connections between brain areas, including feedback from extrastriate to primary striate cortex. The developmental delay seen in even apparently healthy preterms may then be an index of immaturity in these recurrent neural networks. “Dorsal-stream vulnerability” We have emphasized here the capability of the VERP approach to dissect the different levels of the visual hierarchy and their differential value in the analysis of developmental disorders. However, the system is not simply hierarchical but as

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we have discussed above includes parallel pathways. The methods summarized in Table 1 include methods which test mechanisms of form and motion processing both at the V1 level, and at the extrastriate global level and so provide potential assays of the relative development of the parallel dorsal and ventral streams. The chapter by Atkinson and Braddick in this volume introduces the use of global form and motion coherence thresholds to assess the relative development of these streams in Williams Syndrome and other developmental disorders. These perceptual thresholds can be measured in children as young as 4 years old, when presented as a computer game. Children and adults with Williams syndrome were found to be impaired in global motion coherence compared to form coherence, consistent with the severe difficulties in visuospatial cognition which are a feature of their developmental profile. However, the same imbalance was found also in a wide range of other developmental conditions, both those known or believed to be primarily genetic and those, such as hemiplegia, arising from acquired perinatal causes, as listed in Table 3. We have concluded (Braddick et al., 2003) that there exists a general “dorsal-stream vulnerability.” The functions underlying motion coherence sensitivity (and

perhaps, other aspects of dorsal-stream function—see Chapter 15) seem to be more readily disrupted by diverse neurodevelopmental anomalies, than do parallel levels of processing in the ventral stream. We do not yet have a complete account of why this differential vulnerability exists. The developmental pathways which are disrupted are complex ones. If we look at the evidence from normal development, VERP and behavioral studies of infancy show the local cortical analysis of form (orientation) emerging before the local analysis of motion direction (see Fig. 3.) However, global responses to coherence are seen in the motion domain earlier in infancy than in the form domain (Braddick and Atkinson, 2007; Wattam-Bell et al., 2010) and generally, integrative processes based on visual motion are functional very soon after the first development of cortical direction sensitivity (reviewed by Braddick et al., 2003). As global coherence sensitivities develop toward adult values in middle childhood, global motion sensitivity now approaches adult values more slowly, and shows more variability, than global form sensitivity (Atkinson and Braddick, 2005; Gunn et al., 2002). Thus, motion initially lags behind form, then develops more rapidly, and later lags again. We have commented on the reorganization of the

Table 3. Evidence for global motion sensitivity more impaired than global form sensitivity (“dorsal-stream vulnerability”) in developmental disorders Disorder

Origin of disorder

Reference

Young Williams Syndrome children Adult Williams Syndrome Autistic children Hemiplegic children Developmental dyslexics

Genetic: deletion on chromosome 7

Atkinson et al. (1997, 2003)

See above Presumed primarily genetic Acquired: Pre- or perinatal brain injury Presumed partly genetic

Atkinson et al. (2006) Spencer et al. (2000), Milne et al. (2005) Gunn et al. (2002) Cornelissen et al. (1995), Hansen et al. (2001), Ridder et al. (2001) Kogan et al. (2004)

Fragile X Very premature (<33 weeks gestation) Congenital cataract

Genetic: mutation of FMR1 gene on X chromosome. Acquired Acquired

Atkinson and Braddick (2007) Compare Ellemberg et al. (2002) with Lewis et al. (2002)

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extrastriate motion network which appears to take place between the second and third of these stages. More detailed analysis of the developmental course, in both typical and atypical development, is needed to discover whether it is in the course of this reorganization, or earlier, that the developmental pathway is vulnerable to disruption by both genetic and acquired factors.

Conclusion The early and rapid development of vision provides the potential to assay brain development in infancy and to predict broader neurological and cognitive outcomes. By appropriate design and selection of stimulus sequences, VERP methods allow different functional levels and subsystems of the visual brain to be isolated. The levels of the visual pathway are characteristic of particular developmental stages, and the relation between dorsal and ventral streams, indexed by global motion and form sensitivity respectively, appears to be particularly sensitive to neurodevelopmental disorders. In terms of the theme of this volume, we can expect that advances in structural and functional imaging will allow the pathways that transform visual information in the brain to be mapped during both typical and atypical development. Correlated with functional measures like those we have described here, we hope it may be possible to understand points of vulnerability in development, as the genotype of the nervous system unfolds through epigenetic pathways. The better we understand these vulnerabilities, the more effectively we will be able to plan specific therapies and interventions for the young developing child.

Acknowledgments Work reported here was supported by grant G0601007 and previous programme grants from the Medical Research Council.

We thank colleagues and students in the Visual Development Unit for their help and collaboration in the work reported here, in particular Dee Birtles, Shirley Anker, and Jin Lee; and our clinical collaborators in the Hammersmith Hospital, Imperial College London (Eugenio Mercuri, Mary Rutherford, Frances Cowan, David Edwards, Serena Counsell, and Michela Groppo), and the John Radcliffe Hospital, Oxford (Andrew Wilkinson). We are particularly grateful to all the infants and families without whose patient and cheerful cooperation this work would be impossible.

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