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Smaller visual arrays are harder to integrate in schizophrenia: Evidence for impaired lateral connections in early vision.

ABSTRACT: Long-range horizontal connections in early vision undergird a well-studied "collinear facilitation" effect, wherein a central low-contrast target becomes more detectable when flanked by collinear elements. Collinear facilitation is weaker in schizophrenia. Might lateral connections be responsible? To consider the possibility, we had 38 schizophrenia patients and 49 well-matched healthy controls judge the presence of a central low-contrast element flanked by collinear or orthogonal high-contrast elements. The display (target+flankers) was scaled in size to produce a lower and higher spatial frequency ("SF") condition (4 and 10 cycles/deg, respectively). Larger stimulus arrays bias processing towards feedback connections from higher-order visual areas; smaller arrays bias processing toward lateral connections. Patients had impaired facilitation relative to controls at higher but not lower SFs. Combining data from a past study on "contour integration" (in which subjects sought to detect chains of co-circular elements), we found correlated integration and facilitation performance at the higher SF and a similar effect of spatial scaling across SF, suggesting a common mechanism. In an exploratory analysis, worse contrast thresholds (without facilitation) correlated strongly with more premorbid dysfunction. In schizophrenia, inter-element filling-in worsens at smaller spatial scales potentially because of its increased reliance on impaired lateral connections in early vision.

SUBMITTER: Keane BP

PROVIDER: S-EPMC8750297 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThere is mounting evidence that visual perception abnormalities in schizophrenia are partly explained by a dysfunction of the lateral occipital complex (LO). We previously demonstrated that schizophrenia patients had broader topography and reduced magnitude of activity of LO. However, the functional connectivity of LO with other brain regions during visual perception has not been directly investigated in schizophrenia.Materials and methodsEighteen patients with schizophrenia and eighteen matched controls performed a backward masking task during functional magnetic resonance imaging (fMRI). Stimulus onset asynchronies were manipulated to change the level of target visibility. To examine connectivity with LO function we conducted psychophysiological interactions (PPI) analyses using: 1) a region of interest (ROI) approach and 2) a whole brain analysis. ROIs were defined based on a contrast of trials on which a target was presented versus null trials in which no stimuli were presented.ResultsEleven ROIs were identified. Both groups showed similar strength of coupling between LO and the 11 ROIs when visibility was not taken into account. Healthy controls showed clear changes in coupling between LO and prefrontal and parietal regions as a function of target visibility (higher coupling with more visible targets). In comparison, patients showed reduced dynamic coupling with LO in the right superior frontal gyrus (significant after correcting for multiple comparisons) and a trend for reduced coupling in the left precuneus and left inferior frontal regions. Whole brain analysis identified additional regions that showed dynamic coupling with LO in healthy controls, but not in patients.DiscussionThe increased coupling between LO and higher-level parietal and prefrontal regions during visual awareness in healthy controls likely reflects visual reentrant processing. The lack of modulation of coupling between LO and key prefrontal and parietal regions found in schizophrenia may partly reflect abnormalities in LO tuning. The altered LO coupling may contribute to visual perception abnormalities in schizophrenia.

Project description:ObjectiveDecreased density of dendritic spines in adult schizophrenia subjects has been hypothesized to result from increased pruning of excess synapses in adolescence. In vivo imaging studies have confirmed that synaptic pruning is largely driven by the loss of large or mature synapses. Thus, increased pruning throughout adolescence would likely result in a deficit of large spines in adulthood. Here, the authors examined the density and volume of dendritic spines in deep layer 3 of the auditory cortex of 20 schizophrenia and 20 matched comparison subjects as well as aberrant voltage-gated calcium channel subunit protein expression linked to spine loss.MethodPrimary auditory cortex deep layer 3 spine density and volume was assessed in 20 pairs of schizophrenia and matched comparison subjects in an initial and replication cohort (12 and eight pairs) by immunohistochemistry-confocal microscopy. Targeted mass spectrometry was used to quantify postsynaptic density and voltage-gated calcium channel protein expression. The effect of increased voltage-gated calcium channel subunit protein expression on spine density and volume was assessed in primary rat neuronal culture.ResultsOnly the smallest spines are lost in deep layer 3 of the primary auditory cortex in subjects with schizophrenia, while larger spines are retained. Levels of the tryptic peptide ALFDFLK, found in the schizophrenia risk gene CACNB4, are inversely correlated with the density of smaller, but not larger, spines in schizophrenia subjects. Consistent with this observation, CACNB4 overexpression resulted in a lower density of smaller spines in primary neuronal cultures.ConclusionsThese findings require a rethinking of the overpruning hypothesis, demonstrate a link between small spine loss and a schizophrenia risk gene, and should spur more in-depth investigations of the mechanisms that govern new or small spine generation and stabilization under normal conditions as well as how this process is impaired in schizophrenia.

Project description:BACKGROUND:Motivational deficits in people with schizophrenia (PSZ) are associated with an inability to integrate the magnitude and probability of previous outcomes. The mechanisms that underlie probability-magnitude integration deficits, however, are poorly understood. We hypothesized that increased reliance on "valueless" stimulus-response associations, in lieu of expected value (EV)-based learning, could drive probability-magnitude integration deficits in PSZ with motivational deficits. METHODS:Healthy volunteers (n = 38) and PSZ (n = 49) completed a learning paradigm consisting of four stimulus pairs. Reward magnitude (3, 2, 1, 0 points) and probability (90%, 80%, 20%, 10%) determined each stimulus's EV. Following a learning phase, new and familiar stimulus pairings were presented. Participants were asked to select stimuli with the highest reward value. RESULTS:PSZ with high motivational deficits made increasingly less optimal choices as the difference in reward value (probability × magnitude) between two competing stimuli increased. Using a previously validated computational hybrid model, PSZ relied less on EV ("Q-learning") and more on stimulus-response learning ("actor-critic"), which correlated with Scale for the Assessment of Negative Symptoms motivational deficit severity. PSZ specifically failed to represent reward magnitude, consistent with model demonstrations showing that response tendencies in the actor-critic were preferentially driven by reward probability. CONCLUSIONS:Probability-magnitude deficits in PSZ with motivational deficits arise from underutilization of EV in favor of reliance on valueless stimulus-response associations. Confirmed by our computational hybrid framework, probability-magnitude integration deficits were driven specifically by a failure to represent reward magnitude. This work provides a first mechanistic explanation of complex EV-based learning deficits in PSZ with motivational deficits that arise from an inability to combine information from different reward modalities.

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Smaller visual arrays are harder to integrate in schizophrenia: Evidence for impaired lateral connections in early vision.

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