In an investigation of the neurocognitive foundation of impaired spatiotemporal attention in girls with Turner syndrome, we have shown, for the first time, two differences compared to age-matched typically developing girls. The first is that when using a multiple object tracking task designated to assay the capacity and resolution of spatiotemporal attention, girls with Turner syndrome can track one item over space and time as accurately as do their typical peers, but they are significantly impaired when trying to track three items. We suggest that this finding may indicate one of the foundational causes of the spatial, temporal, and numerical impairments that girls and women with Turner syndrome consistently demonstrate and that impairs their ability to function effectively in a manner consistent with their own verbal abilities and with the nonverbal abilities of their unaffected peers. We have also demonstrated functional brain activation differences between girls with Turner syndrome and typically developing controls during the same task, when performance did not differ between the two groups. This finding suggests that despite their overall relatively high level of functioning, girls with Turner syndrome experience an atypical trajectory in the development of neural circuitry capable of implementing spatiotemporal attentional functions and that this hampers the development of typical levels of competence in this domain and in those that depend on it during development.
Comparing the tracking of one out of seven targets to passive viewing of seven objects within groups, we have replicated findings that attentional focus increased activation in the frontal eye fields and the superior parietal lobules (SPL) and precuneus on the medial aspect of the parietal, with activation extending into the inferior parietal lobules (IPL) (e.g., Culham et al., 2001
) and the interparietal sulci (IPS) (e.g., Jovicich et al., 2001
) within the typically developing and Turner syndrome groups. Generally, regions of activation are more diffuse in our pediatric sample compared to the adult sample studied by Culham et al. (2001)
, possibly due to movement within the scanner, a greater ratio of grey to white matter, a propensity to see more white matter activations, and lower BOLD signal-to-noise ratio in children versus adults (Thomason, Burrows, Gabrieli, & Glover, 2005
). As reviewed by Casey, Tottenham, Liston, and Durston (2005)
, cortical function becomes more efficient as the brain matures from childhood through adolescence and into adulthood. Although brain activations appear more diffuse in the current study, the typically developing group clearly demonstrated a “child version” of the expected canonical spatial-attention and memory networks driven by the multiple object tracking task. Given that the typically developing group shows this predicted pattern of activation, we can make stronger inferences about brain activation differences both within the Turner syndrome group and between typically developing girls and girls with Turner syndrome.
Contrasting Turner syndrome and typically developing groups on the one-target tracking task revealed differences in laterality between the groups with greater left SPL activation in the typically developing group, but greater right SPL activation in the Turner syndrome group in the FFX GLM analysis. However, the group differences did not remain significant in the more stringent RFX GLM analysis. This could be a result of lower detection power stemming from the relatively small sample size or possibly because individuals with more atypical BOLD responses are skewing the Turner syndrome group mean in the FFX analysis. Activation of the SPL is generally associated with spatial coding and location discrimination of objects in typical adults (Corbetta, 1998
; Corbetta, Shulman, Miezin, & Petersen, 1993
). Laterality in SPL activation has been reported in elderly adults (Otsuka, Osaka, & Osaka, 2008
), with greater right SPL activation associated with short-term memory storage during a word span test and greater left SPL associated with executive function during a reading span test. Decreased tissue volumes in the right parietal brain region with increased right occipital volume (Reiss, Mazzocco, Greenlaw, Freund, & Ross, 1995
) and with decreased right occipital volume (Murphy et al., 1993
) have also been associated with poorer visuospatial performance in the Turner syndrome population on tasks such as judgment of line orientation (Reiss et al., 1995
). Therefore, greater right SPL activation in the Turner syndrome versus the typically developing group might be indicative of less efficient spatial location processing during the tracking task and could also indicate a reliance on short-term memory strategies and relative impairment in the integration of frontal and parietal circuits. However, given the atypical brain development of the Turner syndrome group, one must be careful about attributing specific locations of brain activations to the functions associated with those areas in typically developing children and adults (Johnson, Halit, Grice, & Karmiloff-Smith, 2002
Greater activation of limbic areas was evident in the Turner syndrome group. The ventralmedial prefrontal cortex (vPFCm) has projections to the amygdala (Quirk, Likhtik, Pelletier, & Pare, 2003
) and activity in the vPFCm at the time of a fear-inducing stressor has been shown to mediate amygdala-dependent fear conditioning in rodent models (Baratta, Lucero, Amat, Watkins, & Maier, 2008
; Quirk et al., 2003
). The Turner syndrome group had greater activity in both the vPFCm and amygdalae than the typically developing group during the one-target task. Furthermore, greater anterior cingulate cortex (ACC) was active in the Turner syndrome group than the typically developing group, whereas greater posterior cingulate cortex (PCC) activity was evident in the typically developing versus the Turner syndrome group. Elevated ACC activation has been reported in females with Turner syndrome in association with completing simple arithmetic (Kesler et al., 2006
). Increased ACC activity has been shown (in typically developing adults) to be negatively correlated with mental exertion and less efficient practice (Raichle et al., 1994
), in anticipation of starting various cognitive tasks (Murtha, Chertkow, Beauregard, Dixon, & Evans, 1996
) and during anticipatory anxiety to electric shocks (Straube, Schmidt, Weiss, Mentzel, & Miltner, 2009
). Therefore, it is not unreasonable to hypothesize that these unusual activations might reflect an increased level of anxiety and negative emotional state in girls with Turner syndrome while they attempt to perform a task that was designed to challenge a domain of neuro-cognitive function that we believe to be foundational to many of their deepest cognitive impairments.
In both the FFX GLM and RFX GLM analyses, the Turner syndrome group showed elevated activation in the left inferior frontal gyrus (IFG) compared to the typically developing group during the object tracking task. Although the Broca's area in this region is known to be critical for speech production, the left IFG is also involved in response inhibition of motor behavior (Swick, Ashley, & Turken, 2008
). Activation of this region in combination with pre- and post-central gyri activations also seen in the Turner syndrome but not typically developing groups may indicate that girls with Turner syndrome may be talking themselves through the tracking task using subvocalizations as a method of proactively preserving short-term memory cues or they may be actively trying to not respond before the allotted times in the task (Delazer et al., 2003
; Kesler et al., 2006
). Again, attributing functions to brain regions in atypical populations can only still be speculative at best because the structure/function relationships evident to be developing in typical individuals can never be taken as the default assumption, especially when it is relatively safe to assume that those with genetic disorders have never experienced a period of typical brain development.
Neural activation differences in the dorsolateral prefrontal cortical (DLPFC) were evident within the typically developing group contrasting one-target tracking and passive viewing but not within the Turner syndrome group. The DLPFC is critically involved in executive functions that support visual–spatial working memory in typical adults, and decreased activation of the DLPFC has been reported with increasing spatial working memory load in females with Turner syndrome (Haberecht et al., 2001
Greater activation to the tracking task also appeared in the occipital cuneus bilaterally and the occipital fusiform gyrus (OFG) in the Turner syndrome group but not the typically developing group. Greater activation in the OFG has typically been shown to occur when viewing coherent object motion (Könönen et al., 2003
The FFX GLM analysis revealed greater activation in the pulvinar in the Turner syndrome group and higher SPL and FEF (corresponding to Brodmann Areas 6 and 8) in the typically developing group. The RFX analysis indicated greater activation in the SPL in the typically developing group and higher activity in the putamen in the Turner syndrome versus the typically developing group. Taken together, this may indicate that a greater portion of the cognitive load associated with the object tracking task is being borne by the developmentally more primitive subcortical system of spatial attention and cognition, whereas in the typically developing group, the cognitive load is carried more by the developmentally advanced frontoparietal network (see Simon, 2008
We recognize several limitations in this study, most especially the reduction in the number of participants that could be included in the final analyses as a result of excessive head motion and/or performance on the task lower than could be ascribed to chance. Lying still in the MRI scanner can be difficult for adults let alone young children. The difficulties associated with acquiring MRI images in children, especially with special populations, typically relate to anxiety regarding the procedure itself, discomfort and boredom, and difficulty self-regulating behavior mean that there will be some degree of data loss. We reiterate that the groups did not differ with regard to data loss associated with motion (ns = 6 in each group). More rigorous tools for reducing head motion through active restraint, such as a bite bar or molded face mask, are likely to contribute to anxiety and discomfort; therefore, we did not use these methods.
We also recognize that contrasting activation and performance across three, two, and one targets, thus increasing task load, would be the optimal experimental design if the girls with Turner syndrome in our sample could be accurate to a level beyond chance. As noted previously, if group performance for the multiple object tracking task is not equitable, it is impossible to attribute group differences in BOLD signal changes to task performance and not some other process, such as anxiety or frustration. However, we believe that the one versus passive contrast is valid because it identifies areas of the brain involved in actively tracking objects. Culham et al. (2001)
also used this contrast to identify which areas of the brain are involved in active tracking of objects. In future studies, researchers could adjust the parameters of the multiple object tracking task to make the task easier for children with Turner syndrome without engendering ceiling performance, and likely minimal cognitive effort, in the typically developing group. Decreasing the speed that targets and distracters move about the screen and lowering the number of distracters could make the task easier for children with Turner syndrome, thus equalizing performance with typically developing children.
In this study, we presented, for the first time, functional brain activation differences in children with Turner syndrome versus typically developing children during a multiple object tracking task. Although children with Turner syndrome were able to complete the object single tracking blocks as well as did typically developing girls, they seem to utilize brain regions somewhat differently than those used by typically developing girls, including subcortical circuits that are more developmentally primitive. Girls with Turner syndrome may also be using alternative strategies for coping with spatial, temporal, and memory information during the multiple object tracking task. These strategies are adequate for relatively simple tasks, such as tracking a single object in a field of distracters, but as cognitive load increases, efficient recruitment of and communication between frontoparietal regions become critical. These inefficient strategies break down when attention and memory load increases, as reflected in much poorer performance by the Turner syndrome group on the three-target tracking component of the multiple object tracking task. We suggest that atypical development neural circuits involved in basic processing of spatial and temporal information in girls with Turner syndrome set the stage for impairments in nonverbal higher order cognitive impairments and typical attention and spatiotemporal competence. Early sources of dysfunction may lie in the alterations in the extent, shape, and patterns of neural connectivity that result in poor handling of spatial-temporal information and/or result in reduced resolution of mental representations of space and time (Simon, 2008