LO is a mid-stage visual processing region that is crucial for target/object awareness and recognition (Green et al., 2005
; Grill-Spector, 2003
; Grill-Spector et al., 2001
; Kourtzi and Kanwisher, 2000
). Here we examined dynamic coupling between LO and other brain regions involved in visual and attentional processing during visual masking in schizophrenia patients and matched controls. Specifically, we used the PPI method with both ROI and whole-brain approaches to evaluate changes in the strength of coupling with LO as a function of target visibility. The ROI approach revealed group differences: patients showed altered dynamic coupling with LO as a function of target visibility in the superior frontal gyrus (significant following correction for multiple comparisons) and trends for left precuneus and left inferior frontal gyrus. Notably, we did not find generally reduced coupling with LO. The whole-brain approach showed significant changes in LO connectivity with target visibility in several parietal and frontal regions for healthy controls, but no regions for patients.
Consistent with the current findings, a separate study of healthy adults used backward masking to measure dynamic changes in coupling between brain areas as a function of visibility (Haynes et al., 2005
). It reported lower visibility was associated with reduced coupling between primary visual cortex (V1) and the fusiform gyrus, and suggested that awareness of a target is associated with coupling between different levels of visual processing. Our findings in healthy controls are consistent with this interpretation because the controls showed increased coupling between LO and parietal and prefrontal regions when the target was visible. Several studies over the last decade have supported the role of prefrontal and parietal regions during visual perception (Kouider and Dehaene, 2007
; Rees, 2007
). Notably, the activity of these higher-level areas is not solely linked to the motor response of subjects reporting their visual experience (Rees, 2007
). However, their precise functional role in visual perception still needs to be clarified. One possible explanation is that LO coupling with higher-level cortical regions reflects feedback signals to visual areas that are referred to as reentrant processing. This type of processing differs from feed-forward processing, a unidirectional processing of information from lower to higher levels in the brain. Visual masking can arise from either feed-forward or reentrant processes and recent evidence suggests that backward masking arises mainly from reentrant processes (Breitmeyer and Ogmen, 2000
; Fahrenfort et al., 2007
). Future studies should use additional connectivity methods that allow inferences about directionality, such as dynamic causal modeling, to confirm whether the altered coupling in schizophrenia reflects feed-forward or reentrant processing abnormalities.
Our finding of altered dynamic coupling in patients is consistent with disconnection theories that posit schizophrenia arises from dysfunctional integration of one or more large-scale distributed brain networks (Calhoun et al., 2009
; Camchong et al., 2009
; Friston, 1998
; Stephan et al., 2009
). Reduced functional connectivity has been observed in schizophrenia between the occipital, parietal and frontal areas (Henseler et al., 2009
). We do not know if the altered coupling we observed is linked to disrupted anatomical connectivity in schizophrenia. This hypothesis can be directly tested by combining masking procedures with techniques such as diffusion tensor imaging that can map white matter tracts (Camchong et al., 2009
; Greicius et al., 2009
). The schizophrenia and control groups did not differ in overall coupling with LO, suggesting that any abnormalities in white matter fibers between LO and the key ROIs, if they exist, are likely to be subtle.
Why might schizophrenia patients show altered dynamic coupling during visual perception? The three ROIs that showed altered coupling with LO in schizophrenia have several functions. The precuneus has been implicated in episodic memory retrieval, self processing, consciousness, and visuo-spatial information processing, including preparation of spatially guided behaviors (Cavanna and Trimble, 2006
). The inferior and superior frontal gyri (i.e. mainly dorsolateral prefrontal cortex/BA 9) have a role in executive functions, attention regulation, and motor planning (Alvarez and Emory, 2006
; Robertson et al., 2001
). The impaired coupling between LO and these three regions could be due to a problem with higher-level top down processes, or due to intrinsic abnormalities in LO. However, the current study is not able to distinguish between these two possibilities. It should be reminded that two of the ROIs, the left precuneus and left inferior frontal, did not survive a Bonferroni correction for multiple comparisons. Hence, additional studies will be required to confirm the altered coupling of these two ROIs with LO in schizophrenia patients.
For our connectivity analyses we decided to include participants with bilateral functional LO (27 participants) as well as participants with unilateral functional LO (9 participants). One might wonder whether our connectivity results would have been different if we had analyzed the left and right LO separately. Hence, we conducted post-hoc analyses for the left and right LO. Specifically, we evaluated group differences in coupling with each of the 3 ROIs that showed group differences for the main analysis. For left LO, results were fairly similar to the main analysis, with patients showing significantly altered coupling with the left precuneus (p=0.003), and at trend level for the left inferior frontal (p=0.12) and right superior frontal (p=0.06). For the right LO, patients showed significantly altered coupling only with the right superior frontal only (p=0.04). The other two ROIs were not significant (left precuneus–p=0.57; left inferior frontal–p=0.25). These post-hoc analyses suggest that the significant effects observed in two of the ROIs (left precuneus and left inferior frontal) were mainly due to the influence of the left LO. However, the other ROI (right superior frontal) was significant likely because of the influence of both left and right LO.
The groups did not differ in their performance during the visual masking task. At first glance, this appears to be inconsistent with performance data from many previous studies (Butler et al., 2003
; Cadenhead et al., 1998
; Green et al., 2003
; McClure, 2001
). The methods we have used in our published performance studies were optimized to show group differences. The target stimuli are small (0.24° of visual angle) and are shown at visual threshold so that all of the subjects are equated for initial sensory input. In contrast, the masking methods in the present report were optimized to elicit regional brain activity in the scanner. Stimuli were large (target=5.7°, mask=10.2°), dark with high contrast, and well above threshold for identification. Hence, the target in this fMRI study was about 24 times as large as in our performance laboratory studies. Although the absence of performance differences is unusual in the context of the masking literature, it provides an interpretive advantage in that performance level is not a confound in considering group differences in regional brain activity and coupling. It remains possible that the lack of significant performance difference indicates that the patients in this study are atypical. As described in our previous paper (Green et al., 2009
), we examine this possibility by evaluating data from a subset of patients (n=10) and controls (n=17) who were also examined on visual masking performance out of the scanner. The between-group effect sizes for these subjects were highly consistent with what is found in other studies. Hence, we do not consider the patient sample to be unusual in this regard.
We also made the methodological decision of using the same psychological regressor for all subjects (i.e. coding SOAs 1 and 2 as a low visibility; SOAs 3 and 4 as a high visibility). This choice was based on the mean performance data from both groups. We cross-checked this cut-off to see whether many subjects would not fit this performance pattern -- we calculated for each subject the difference in performance between high and low visibility (i.e. mean accuracy for SOA 3–4 minus SOAs 1–2). The range of difference scores for patients (0.31 to 0.56) and controls (0.31 to 0.66) indicated that, although subjects differed somewhat in their performance across SOAs, this general psychological regressor was a very good approximation of the change in target visibility for these two samples.
All patients were on antipsychotic medications at the time of the scan. The real impact of medication on our connectivity results is not easy to evaluate. It is possible that antipsychotics that block dopamine receptors have contributed to the altered coupling of LO during visual perception in schizophrenia. However, there is evidence that antipsychotic medications tend to normalize functional connectivity in schizophrenia patients (Stephan et al., 2001
). Moreover, masking deficits have been reported in unmedicated patients (Green et al., 1999
). It suggests that the masking impairment in schizophrenia, and its neural correlates, are unlikely to be explained by medication.
One can speculate on the meaning of these results for previously reported findings of blunted LO response and increased LO topography in schizophrenia (Green et al., 2009
; Wynn et al., 2008
). The blunted response may create a situation in which coupling with LO cannot be established because it requires a certain threshold in activation that is not achieved. However, the beta weights in are not consistent with this suggestion; patients showed a lack of change in coupling across visibility conditions, not a general reduction of LO connectivity. The widespread topography of LO in schizophrenia could possibly be explained by less specialization of cortex or compensatory activation within LO. It may be that neurons in LO are less specialized, so more of them respond regardless of object visibility. Such a suggestion would be consistent with an abnormality in “tuning” of LO. That is, LO in patients may be less efficient at distinguishing between visual targets and visual noise (i.e. impaired filtering of relevant vs. non-relevant information from the visual environment) leading to a general lack of modulation of coupling as a function of visibility. In fact, patients showed relatively high coupling between LO and the three ROIs during low target visibility. Possibly due to better LO tuning, healthy controls could more easily reduce coupling between LO and the higher-level areas when targets are not perceived, and increase coupling when targets are detected. Conversely, impaired LO tuning and associated reduced dynamic changes in coupling as a function of visibility might be the basis of visual processing abnormalities in schizophrenia patients.
The suggestion that altered modulation of connectivity is linked to an abnormality in LO tuning connects well to current theories of GABA function. There is compelling support for GABA abnormalities in schizophrenia, particularly interneurons that express the calcium-binding protein parvalbumin (Lewis et al., 2005). The GABA interneuron abnormalities in schizophrenia occur across the cortex, including the primary visual area (Hashimoto et al., 2008), and they lead to specific predictions for visual processing. A recent MR spectroscopy study showed a reduction in GABA concentration in visual cortex in schizophrenia (Yoon et al., 2010). A key role for GABA in the visual system is to aid the tuning of individual neurons, and the importance of GABA for tuning likely increases as one moves up the processing hierarchy from V1 to LO (Kritzer et al., 1992). Tuning in this context refers to the graded pattern of selectivity for specific visual features that is shown by neurons in visual cortex. In the monkey, when a GABAA receptor antagonist is applied to neurons in the comparable object-selective region, they lose tuning and respond to objects that do not elicit a response before or after the drug administration (Wang et al., 2000). The fact that patients maintain high coupling even when a target is not visible may reflect an abnormality in LO tuning, which in turn, could stem from GABA dysfunctions.
This study suggests that visual perception abnormalities in schizophrenia may involve an altered modulation of coupling between LO and higher-level visual and attentional brain regions. Additional neuroimaging studies with more specialized procedures will shed light on potential LO tuning abnormalities in schizophrenia, and their possible link to altered functional connectivity. One promising line of future inquiry will be to use the pattern-based decoding approaches (i.e. multi-voxel pattern analysis) and MR adaptation paradigms to further probe neural tuning in LO.