Aberrant Cortical Connectivity during Ambiguous Object Recognition is Associated with Schizophrenia

Abstract

Background:

Dysfunctional connectivity within the perceptual hierarchy is proposed to be an integral component of psychosis. The fragmented ambiguous object task (FAOT) was implemented to investigate neural connectivity during object recognition in patients with schizophrenia and bipolar disorder and first-degree relatives of patients with schizophrenia.

Methods:

We analyzed 3T fMRI data from 27 patients with schizophrenia (SCZ), 23 patients with bipolar disorder (BP), 24 controls and 19 first-degree relatives of SCZ (SREL) collected during administration of the FAOT. FAOT stimuli were line-segmented versions of objects and matched across a number of low-level features. Images were categorized as meaningful or meaningless based on ratings made by participants.

Results:

An a priori region of interest was defined in the primary visual cortex (V1). Additionally, the lateral occipital complex/ventral visual areas (LOC+), intraparietal sulcus (IPS), and middle frontal gyrus (MFG) were identified functionally via contrast of cortical responses to stimuli judged as meaningful and meaningless. SCZ was associated with altered neural activations at V1, IPS and MFG. Psychophysiological interaction analyses revealed negative connectivity between V1 and MFG in patient groups and altered modulation of connectivity between conditions from right IPS to left IPS and right IPS to left MFG in SCZ and SREL.

Conclusions:

Results provide evidence that schizophrenia is associated with inefficient processing of ambiguous visual objects at V1 that is likely attributable to altered feedback from higher-level visual areas. We also observed distinct patterns of aberrant connectivity between low, middle, and high-level visual areas in SCZ, BP and SREL.

Introduction

Psychosis is commonly associated with altered perceptual processes both experimentally and phenomenologically. Visual abnormalities in psychosis are especially pronounced in schizophrenia, but have also been reported in patients with bipolar disorder and first-degree relatives of patients with schizophrenia (1,2). Past research has largely failed to elucidate the mechanisms by which perceptual abnormalities in these groups lead to (or result from) the heterogeneous clinical and subclinical symptomatology associated with psychosis and genetic predisposition for psychosis; however, recent Bayesian predictive coding models compellingly describe how aberrant top-down modulation (e.g. decreased precision of priors) and overreliance on bottom-up sensory information (e.g. increased precision of likelihood) may lead to a variety of psychotic symptoms including positive, negative and interpersonal symptoms (3-5). Although predictive coding frameworks may be useful for understanding the relationship between neurobiology and psychopathology, the validity of such models is dependent upon developing a better understanding of the neural pathways and architectures involved in perception. Thus, neuroimaging and electrophysiology experiments elucidating the nature of information flow between levels of perceptual hierarchies in the brain will be crucial for the advancement of such models.

Experimentally, the majority of assays of perceptual processing deficits in psychosis have focused on questions of where and when in the perceptual stream deficits occur (e.g. low-level vs. high-level, early vs. late). Decades of such investigations have not produced a smoking gun; instead there is evidence for processing abnormalities at multiple time points and locations in the perceptual stream (6-10). This is unsurprising given perception is thought to be the result of iterative loops of bottom-up and top-down signals that coordinate and modulate information flow between brain regions (11). As such, there is a need for investigations of interactions between low-level, mid-level and high-level perceptual processes to better understand perceptual impairments in psychosis.

The primary visual cortex (V1) in particular is a promising candidate for exploring interactions between feedforward and feedback signals (12). Although V1 is commonly thought of as a simple retinotopic map that receives input from the lateral geniculate nucleus (LGN), only ~10% of connections to V1 are inputs from the LGN (13). The remaining connections consist of feedback connections from other brain regions and long-range horizontal connections within V1 both of which are thought to modulate neuronal activation in V1 (11). For example, V1 BOLD activation to line drawings has been shown to be dependent upon higher-level shape perception in the lateral occipital complex (14). Meaning, observed V1 BOLD activation is likely the result of interactions between feedforward and inhibitory feedback connections.

A significant obstacle in successfully characterizing the influence of higher level brain regions on the primary visual cortex is the dearth of image sets that range in high-level features while controlling for low-level features. The present study implemented a previously published set of images designed for this purpose (15), originally inspired by the work of Cardin, Zeki and Friston (12). The set of images depicts fragmented ambiguous objects that vary in the high-level property of recognizability (i.e. some objects are easier to discern than others), but are matched for low-level properties including image luminance, total number of line segments in the image, orientation distribution of line segments, number of line terminations, and contour probability (see (15) for more details). Leveraging the well-characterized tuning properties of neurons in V1, we assume that changes in V1 activation in response to these images are likely the result of higher-level feedback connections rather than differences in feedforward input from LGN. Given that psychosis is thought to be associated with reduced top-down inhibitory feedback, it is possible that the expected reduction in V1 activity for more recognizable stimuli (14) would be diminished in patients compared to controls.

The present study explored associations between low, middle and high-level visual areas, and a spectrum of psychosis by acquiring functional magnetic resonance imaging (fMRI) data during viewing of fragmented ambiguous objects across a transdiagnostic sample of patients with schizophrenia, patients with bipolar disorder, first-degree relatives of patients with schizophrenia and healthy controls. Specifically, we hypothesized that V1 activation would be affected by feedback from middle- and high-level visual areas and that psychosis would be associated with larger V1 activation to meaningful relative to meaningless stimuli from the Fragmented Ambiguous Object Task (FAOT) consistent with a predictive coding account of psychosis in which top-down inhibitory feedback (instantiated here as object recognition in LOC and/or other high level regions) is diminished.

Methods and Materials

Participants

34 SCZ, 25 BP, 25 CON, 20 first-degree relatives of SCZ were recruited through the Minneapolis VA Medical Center, community mental health programs, and fliers posted throughout the community. Participants with a psychiatric diagnosis were stable outpatients. Exclusion criteria for SCZ, BP and CON included intellectual disability (IQ <70), drug or alcohol dependence in past 6 months, current or past central nervous system condition, epilepsy, history of electroconvulsive therapy, history of head injury with skull fracture or loss of consciousness longer than 30 minutes, age under 18 or over 60, and all standard MRI contraindications. CON were also excluded if they had a history of primary psychotic disorder, current or past depressive episode, ADHD or learning disability or family history of depression, schizophrenia or bipolar disorder. SREL were only excluded if they had a general medical condition that made study completion impossible. All procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.

Participants’ IQ was estimated using the Wechsler Adult Intelligence Scale III (WAIS-III) Vocabulary and Block Design subtests. Psychiatric symptom severity was assessed via the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I (16)) and the Brief Psychiatric Rating Scale (BPRS (17)). Nine of the 23 BP endorsed a previous psychotic episode. The Schizotypal Personality Questionnaire (SPQ (18)) was administered to all participants to characterize subclinical psychotic symptomatology. A minimum of two trained raters (advanced doctoral students in clinical psychology, postdoctoral researchers, or licensed doctoral-level psychologists) reached consensus on all diagnoses.

Stimuli

Stimuli were presented using PsychoPy on an iMac running MacOS 10.9 and were projected using a NEC NP4100 projector with a resolution of 1024x768 pixels and a 60 Hz refresh rate (19). Images were back-projected onto a translucent screen placed inside the scanner bore and were viewed through a mirror mounted on the head coil, positioned over participants’ eyes. Viewing distance was 112 cm, images subtended 8° of visual angle and the mean luminance of the projected image was 110 cd/m².

Stimuli were generated by converting publicly available images of objects into spatially discrete line segments by applying a filter that emulates preferred orientation tuning in V1. Line segments representing the dominant orientation of local features sampled on a regular grid were then embedded in a background of parallel line segments. The orientation of parallel background line segments was determined randomly for each image. All line segments had a length of seven pixels and the total image size was 384x384 pixels. See Figure 1 for stimulus examples.

Figure 1. Stimulus Examples.

Stimuli were generated by converting publicly available images of objects into spatially discrete line segments by applying a filter that emulates preferred orientation tuning in V1. Participants rated images as “short and fat” (right button press) or “tall and skinny” (left button press). Adapted from Figure 1 in (15).

Images were categorized as meaningful or meaningless based on the recognizability of the embedded objects. Initially, images were categorized based on yes/no recognition ratings from four study staff (39 participants viewed this version of the task). For the remainder of the study, images were categorized based on yes/no recognition ratings made by participants themselves in a separate behavioral iteration of the task. This second categorization method was implemented to ensure the ratings of stimuli reflected the recognition rates of the population of interest. For both the initial study staff categorizations and the participants’ categorizations, the 63 images that were most frequently rated as recognizable were categorized as meaningful and 60 images that were most frequently rated as unrecognizable were considered meaningless. Only 6.5% (8 out of 123) of the images were categorized differently between study staff and participants. For more information regarding stimuli creation and properties see (15).

Fragmented Ambiguous Object Task

The task consisted of three conditions: meaningful, meaningless and rest. Participants were presented with a total of 26 blocks (nine blocks per stimulus condition; eight blocks of rest) for a total scan duration of 312s; block order was determined by an m-sequence (20). Each block was 12s long and was composed of eight trials (1.5s duration each). Each stimulus was presented for 1s followed by 0.5s of blank screen before the next trial. Stimuli were sampled randomly with replacement within the given condition.

Subjects were asked to indicate whether the fragmented ambiguous objects presented to them were “tall and skinny” or “short and fat” by pressing the left or right button, respectively, on a fiber-optic button box (Current Designs, Philadelphia, PA). This behavioral task was designed to ensure participants engaged meaningfully with stimuli without activating overt object identification (i.e., naming) processes. By employing this behavioral paradigm, we sought to eschew semantic processing and isolate brain activations that reflected naturalistic object perception.

fMRI acquisition and preprocessing

Functional MRI data were collected using a 3T Siemens Prisma system (Siemens, Erlangen, Germany) with a 32-channel head coil. Whole brain EPI data were acquired with a field of view of 208mm and a matrix size of 88x88, resulting in an in-plane resolution of 2.4mm isotropic. Sixty slices were collected every 1.5s. Echo time (TE) was 30ms and the flip angle was 75°. Data were collected in the transverse orientation and the phase encode direction was anterior-posterior. A T₁-weighted anatomical volume (MP-RAGE) with 1 mm isotropic resolution was collected sagittally for anatomical reference.

Functional data were preprocessed using Analysis of Functional NeuroImages software (21). For each scan, the initial EPI was used as a reference volume for motion correction. Motion corrected data were then unwarped with a reverse phase encode EPI via AFNI’s 3dQwarp function. Functional data were aligned with anatomical scans using AFNI’s 3dAllineate and spatially smoothed (FWHM=2 mm).

Analysis

Subjects were excluded from analysis for response rates below 60%, statistically nonsignificant V1 responses or if greater than 30% of TRs contained significant movement (defined as greater than .5mm). Analyses were performed on the remaining 27 SCZ, 23 BP, 24 CON, and 19 SREL. A priori V1 ROI’s were defined by computing the intersection of significant positive whole brain voxel activation and individualized probabilistic maps of V1 (22). Post hoc ROI’s were identified by contrasting meaningful and meaningless conditions across participants. Six post hoc ROI’s were identified this way: right and left lateral occipital complex with additional activation in the fusiform gyrus (LOC+), right and left intraparietal sulcus (IPS), and right and left middle frontal gyrus (MFG). Alpha for all ROI’s was set at .001 voxelwise probability and .01 clusterwise probability with a minimum cluster size of 23.

To characterize stimulus-dependent connections between ROIs, we computed generalized psychophysiological interaction (gPPI) terms for V1, r/lLOC+, r/lIPS and r/lMFG (23). The gPPI approach has been shown to be especially powerful for block design tasks such as the FAOT (24). False discovery rate (FDR) corrected p-values were calculated via the p.adjust function in R.

Results

Demographic, Clinical & Behavioral Measures

Participant demographic information is presented in Table 1. Visual acuity and age did not differ across groups. SCZ exhibited lower IQ and reported fewer years of education as compared to CON. SCZ exhibited the most symptomatology as indicated by highest totals on the BPRS and SPQ, with BP rated second highest and SREL totals falling between CON and BP. SCZ gender distribution skewed more male than any of the other groups with post hoc pairwise comparisons revealing a significant difference between SCZ and SREL. To partially account for this imbalance in gender distribution, all reported repeated measures ANOVAs (RM-ANOVAs) included gender as a between-subjects factor. Visual acuity was included as a covariate in all models to account for variance that might be attributed to low level differences in sensory processing. 20 SCZ and 15 BP were taking antipsychotic medication with SCZ taking higher chlorpromazine equivalent doses than BP. We did not observe any significant correlations between chlorpromazine equivalent dose and any neural measures (Figure S2).

Table 1.

Participant Demographic Characteristics and Symptom Ratings

Index	SCZ (n =27)	BP (n =23)	CON (n =24)	SREL (n =19)	Statistics	Post Hoc Contrasts
Age	43.52 (9.61)	45.22 (11.36)	47 (9.58)	46.8 (9.58)	F (3,89) =.65, p = .59
Percent Female	19%	48%	46%	74%	X2(3) =14.07, p =.002	SCZ<SREL
Education	13.56 (2.24)	15.04 (2.6)	15.92 (1.14)	14.8 (2.0)	F (3,89) =5.68, p =.001	SCZ<CON
Estimated IQ (from WAIS-III)	98.33 (15.05)	103.04 (13.91)	113.12 (12.46)	109.11 (17.87)	F (3,89) =4.83, p =.004	SCZ, BP<CON
CPZ Equivalent	10.6 (18.41)	1.85 (1.33)			T (19.2) =2.12, p =.04	BP<SCZ
Visual Acuity (LogMAR)	0.12 (0.14)	0.11 (0.13)	.07 (.13)	.12 (.12)	F (3,89) =.56, p = .639
Overall Symptomatology (BPRS Total)	39.37 (8.83)	36.3 (8.96)	25.7 (2.0)	30.9 (8.18)	F (3,89) =15.77, p<.001	CON<SCZ,BP,SREL SREL<SCZ
BPRS Positive	8.81 (4.32)	5.78 (1.13)	5.04 (0.2)	5.74 (2.54)	F (3,89) =10.28, p<.001	CON<SCZ,BP SREL<SCZ
BPRS Negative	3.93 (1.27)	3.87 (1.71)	3.17 (0.48)	3.21 (0.71)	F (3,89) =2.91, p=.039	CON<SCZ
BPRS Disorganized	7.07 (2.07)	6.26 (1.74)	4.38 (0.77)	5.74 (1.7)	F (3,89) =11.76, p<.001	CON<SCZ,BP, SREL, SREL<SCZ
Schizotypal Characteristics (SPQ Total)	36.6 (16.5)	23.78 (15.41)	7.4 (6.3)	18.4 (13.2)	F (3,86) =15.14, p<.001	CON<SCZ,BP,SREL SREL,BP<SCZ
SPQ Cognitive Perceptual	14.12 (9.23)	8.7(7.26)	1.17 (1.56)	5 (5.65)	F (3,86) =16.23, p<.001	CON<SCZ,BP,SREL SREL,BP<SCZ
SPQ Disorganized	6.44 (4.48)	6.83 (3.81)	1.39 (1.5)	3.53 (3.85)	F (3,86) =11.72, p<.001	CON<SCZ,BP,SREL SREL<SCZ, BP
SPQ Interpersonal	17.68 (8.5)	11.09 (9.02)	4.91 (4.96)	11.84 (7.62)	F (3,86) =10.99, p<.001	CON<SCZ,BP,SREL SREL,BP<SCZ

All data are presented as Mean (Standard Deviation), unless otherwise noted. SCZ = patients with schizophrenia , BP = patients with bipolar disorder, SREL = first degree relatives of SCZ, CON = healthy controls. WAIS-III = Wechsler Adult Intelligence Scale, 3rd edition. 20 SCZ and 15 BP were taking antipsychotics. BPRS = 24-item brief psychiatric Rating Scale. SPQ = Schizotypal Personality Questionnaire. Alpha for all post hoc contrasts was set at .05 and p-values were FDR corrected for multiple comparisons when appropriate. SPQ Total data were not obtained for two SCZ and one CON.

Behaviorally, we did not observe any differences in left button (i.e. tall and skinny) vs. right button (i.e. short and fat) responding between groups (interaction of group and response-type, ANOVA, F(3, 88) = 1.09, p = .359, η2 = .03). Furthermore, we did not observe strong evidence of differences in frequency of responses between groups (main effect of group, F(3, 88) = 2.55, p = .061, η2 = .01) nor differences in distribution of responses between groups (Levene’s test of equal variances, F(3,180)=0.71, p=.546; see Figure S4).

V1 BOLD activation

At V1 (see Figure 2), we observed a difference between groups in the amount of BOLD modulation between conditions (interaction of group and condition, ANOVA, F(3,87)=3.30, p=.024, η2=.10 ). This interaction was driven by SCZ who were the only group to exhibit significantly larger activations during the meaningful condition relative to the meaningless condition (FDR corrected p=.003). We did not observe significant main effects of condition or group on V1 BOLD activations. We then correlated meaningful-meaningless difference scores with scores on the SPQ and BPRS, but these correlations did not reach significance. Additionally, IQ was not correlated with V1 difference scores, providing evidence that the group by condition interaction was not driven by a generalized deficit.

Figure 2. V1 BOLD activation.

[Panel A] Depiction of an example V1 ROI for a single participant. Individualized probabilistic maps of V1 (22) were restricted to positive clusters of voxels that modulated significantly between resting and meaningful+meaningless conditions. [Panel B]. V1 BOLD activation for each condition and group. Error bars are within-subjects standard error of the mean with a Morey correction factor according to an established method (37). [Panel C] To characterize how a spectrum of clinical and subclinical psychotic symptoms relate to task manipulations, we correlated meaningful-meaningless difference scores with SPQ totals.

Post hoc ROIs

It should be noted that RM-ANOVAs revealed significant main effects of condition for all post hoc ROIs because these ROIs were selected based on statistically significant modulation between conditions. Laterality was included as a within subjects variable for all post hoc ROI RM-ANOVAs. Figure 3 depicts all post hoc ROIs and mean BOLD activation per group, per condition.

Figure 3. Post Hoc ROIs.

[Panel A] Depictions of group-level ROIs that significantly modulated BOLD activation between meaningful and meaningless conditions. Left lateral occipital cortex + ventral visual areas (lLOC+; dark blue), right LOC+ (yellow), left middle frontal gyrus (lMFG; teal), rMFG(orange), left intraparietal sulcus (lIPS; green), rIPS (red). [Panel B] Post hoc ROI BOLD activations for each condition and group. * indicates significant interaction of group and condition. Similar to Figure 2, error bars are within-subjects standard error of the mean.

We did not observe a main effect of group or interaction of group by condition on LOC+ activation. There was a significant interaction between condition and laterality(F(3,87)=8.73, p=.004, η2 = .09) that was driven by larger condition modulation in right LOC+ as compared to left LOC+. We observed a difference in IPS activation between groups as a function of condition in IPS (group by condition interaction, F(3,87)=3.78, p=.014, η2 = .12) that was driven by stronger modulation between conditions in SCZ and SREL compared to other groups. For MFG, we also observed an interaction of group and condition (F(3,87)=4.57, p=.005, η2 = .14). Follow-up examination revealed again that SCZ and SREL exhibited the strongest modulation between conditions. Additionally, there was a main effect of laterality in which left MFG exhibited stronger activation as compared to right MFG across groups (F(3,87)=6.64, p=.012, η2 = .07). IQ, SPQ and BPRS scores failed to correlate with meaningful-meaningless difference scores in IPS or MFG.

Context-dependent interactions (gPPI)

We quantified a total of 42 connections of interest by assigning each ROI (V1, r/lLOC+ r/lIPS and r/lMFG) as a seed region and computing interactions with the 6 remaining ROIs (7 seed regions x 6 ROIs) per condition per subject. We then tested the effect of condition for each gPPI connection of interest (COI) via dependent samples t-tests. 19 out of the 42 COIs showed a significant effect of condition after FDR correction for multiple comparisons (ps<.001). Figure 4A depicts this subset of COIs selected for further analysis. Although one cannot infer biological directionality from gPPI, we use arrows to illustrate the statistical directionality of gPPI results, e.g., if the connection between seed region rLOC+ to target region V1 is significant we cannot assume that the connection between seed region V1 to target region rLOC+ is also significant.

Figure 4. gPPI Results.

[Panel A] Cartoon depiction of the 19 connections that showed significant modulation between meaningful and meaningless conditions organized into ventral and dorsal connections. [Panel B] Tile plot showing results of the first mass univariate analysis in which each connection for each condition for each group was tested against zero. Asterisks indicate significance at p<.05 after FDR correction for multiple comparisons.

To investigate connection strength within each group, we implemented a mass univariate approach in which we ran one-sample t-tests against zero for each group for each condition for the 19 COIs selected for further analysis, correcting for multiple comparisons via FDR (Figure 4B). In the context of gPPI, running one sample t-tests against zero for each interaction beta weight tests the null hypothesis that connection strength did not change during stimulus presentation.

COIs with V1 as the seed region showed varied patterns of activation across groups. SCZ and BP groups exhibited significant, negative V1→-lMFG connections for the meaningless condition while all groups except SCZ significantly increased connection strength from V1→r/lLOC during the meaningful condition. CON were the only group to increase V1→rIPS connection strength. For midlevel ventral (i.e. LOC+) seed COIs, all groups but CON exhibited increased connectivity from r/lLOC→V1. All midlevel IPS seed COIs were significant for all groups except for rIPS→r/lMFG in which SREL were the only group to increase connection strength between rIPS→lMFG. Finally, all groups exhibited a significant increase in connectivity relative to resting for all high-level (i.e. MFG) seed COIs.

To directly explore group differences and isolate task-related connection strengths that were specific to condition manipulation (meaningful vs. meaningless) rather than general visual system activation (resting vs meaningless or resting vs. meaningful), we ran RM-ANOVAs with group as a between subjects factor and condition as a within subjects factor. We observed an interaction of group by condition at rIPS→lIPS (F(3,87)=4.7, p=.004, η2 = .14) and rIPS→lMFG (F(3,87)=3.74, p=.014, η2 = .11) that were both driven by SCZ and SREL modulating connectivity more between condition than the other groups (see Figure 5). Additionally an interaction of group by condition at lMFG→lLOC (F(3,87)=3.48, p=.019, η2 = .11) was driven by SREL who exhibited a lack of modulation between conditions compared to the other groups (Figure 5). We did not observe any other group or group by condition effects.

Figure 5. gPPI Connections Showing a Group by Condition Interaction.

3 COIs showed significant differences between conditions as a function of group. Interactions were primarily driven by altered modulation in SCZ and SREL. Similar to Figure 2 and 3, error bars represent within-subjects standard error of the mean.

Finally, to explore relationships between neural measures and symptom severity, we computed mass correlations between all neural measures of interest (i.e. individual ROI activations, connectivity indices and meaningful-meaningless subtraction indices) and SPQ and BPRS scores corrected for FDR. These exploratory mass correlations are depicted in supplemental figure S2.

Discussion

Summary

The present study identified neural correlates of fragmented ambiguous object recognition in a transdiagnostic sample of patients with schizophrenia, patients with bipolar disorder, first-degree relatives of patients with schizophrenia and healthy controls. We found that SCZ was associated with altered V1 activations during object recognition. We identified bilateral mid-level visual areas in both the ventral (r/lLOC+) and dorsal (r/lIPS) stream, and bilateral high-level areas (r/lMFG) that modulated between meaningful and meaningless conditions and found that SCZ and SREL exhibited stronger modulation between conditions at IPS and MFG. Finally, we characterized distinct patterns of functional connectivity between ROIs for each group.

Low-Level ROI: V1

Because image sets were painstakingly matched for low-level features, including likelihood of collinear elements, modulation of V1 between conditions was likely a result of feedback from higher visual areas. SCZ exhibited patterns of V1 activation between conditions that were distinct from SREL, BP and CON. This finding is consistent with a predictive coding account of schizophrenia in which aberrant predictive coding (instantiated here as aberrant feedback connections between brain regions) leads to (or stems from) downstream cognitive-perceptual distortions. However, it must be noted that we did not observe correlations between meaningful-meaningless difference scores and symptom severity ratings.

Our results shed light on previous studies of the modulatory effect of context and shape perception on V1 activation in normative populations (14,25-29). For example, Murray et al. (2002) observed strongest V1 activation to stimuli composed of randomly oriented lines (i.e. meaningless line drawings) and weakest activation to stimuli composed of lines grouped into 3 dimensional shapes (i.e. meaningful line drawings). We did not observe this pattern of activation in CON, BP or SREL and observed the opposite pattern in SCZ (i.e. greater activation to meaningful stimuli). These findings build upon the work of Qiu et al. (2016) which showed that previous discrepancies in the literature (see: (14,25,26)) were likely due to differences in amount of visual clutter and contour alignment. Crucially, the FAOT stimuli were matched for both of these confounds and thus provide a novel account of the effect object recognition on V1 activation.

Mid-level ROIs: LOC+ and IPS

V1 participates in both ventral and dorsal visual streams with ventral activation commonly associated with identification/recognition processes and dorsal activation associated with location-oriented and behavior guidance processes. We did not observe strong evidence of deficits in mid-level ventral (LOC+) BOLD activation and instead found evidence of altered mid-level dorsal (IPS) BOLD activation in SCZ and SREL. These results align with previous findings of aberrant dorsal stream visual processing in SCZ during fragmented object recognition (10,30). For example, Doniger, et al. (2002) reported intact ventral N1 component, but altered dorsal P1 component generation in SCZ during an object recognition task measured via electroencephalography. This convergent evidence across neuroimaging modalities and tasks suggests that IPS plays an important role in dysfunctional object recognition in SCZ and may extend to those with a genetic liability for schizophrenia (i.e. SREL). It is worth noting that others have observed ventral object processing deficits in schizophrenia (31), however this discrepancy is likely due to substantially different experimental manipulations and less well-controlled visual stimuli.

High-level ROI: MFG

Similar to IPS, we observed stronger MFG modulation between conditions in SCZ and SREL. MFG is commonly linked to the ventral attention network and is thought to play a role in re-orienting attention (32). Thus, larger decreases in MFG activation to meaningless stimuli relative to meaningful in SCZ and SREL may reflect reduced ability to allocate attention to more ambiguous stimuli.

Connectivity

We quantified task-dependent connectivity between ROIs (i.e. V1, r/lLOC+, r/lIPS and r/lMFG) to clarify visual network activity during ambiguous object recognition. Across all participants, 19 of the 42 connections strongly modulated between conditions. 10 of these COIs shared striking similarities to proposed hierarchical models of the ventral stream in which V1 and LOC+ share information bidirectionally, consistent with feedforward and feedback between these regions (11,33,34). It is important to note that the significance of unidirectional vs. bidirectional connectivity between regions in the context of gPPI is still unknown. gPPI terms certainly reflect a “statistical directionality”, in that a seed area and target area are defined and cannot be assumed to be commutative; however, whether this statistical directionality can be translated to biological directionality is controversial. Previous studies have successfully used dynamic causal modeling to validate directionality of gPPI-derived connections (35); however dynamic causal modeling itself has considerable limitations (36).

Mass univariate t-tests of context-dependent interaction beta weights against zero revealed opposing connectivity between V1 and MFG for SCZ and BP which is consistent with overreliance on low-level, sensory processes in these groups. Additionally, SCZ were the only group that failed to increase connection strength from V1→r/lLOC during the meaningful condition consistent with reduced feedback from midlevel ventral regions although follow up RM-ANOVAs did not reveal a significant effect of group or a group by condition interaction. Finally, we observed stronger modulation between conditions in SCZ and SREL of rIPS→lIPS and rIPS→lMFG suggesting altered dorsal stream processing may be a feature of genetic predisposition for schizophrenia.

Conclusions

To our knowledge, this is the first study to assess the neural correlates of object recognition across a spectrum of psychosis using images that are matched for low-level features. Our results provide evidence that BOLD activation at V1 is modulated by other visual areas in SCZ which has broad implications for the study of vision in SCZ and emphasizes that no brain region in the visual hierarchy can be considered an island. Clinically, the present study identified aberrant processing of visual information in the dorsal stream and prefrontal regions in schizophrenia and relatives of patients with schizophrenia. Our findings highlight that schizophrenia is likely not the result of isolated low- or high-level perceptual deficits, but of aberrant connectivity between levels of the perceptual hierarchy.