Rebecca A Berman’s research while affiliated with National Institute of Mental Health, National Institutes of Health and other places

Background Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity anomalies affect the neural substrates of social perception remains unknown. Here we measure these relationships using functionally based localization of social perception areas, resting-state functional connectivity, and movie-watching data. Methods In 42 schizophrenia participants (SzP) and 41 healthy controls (HC), we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind, and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal theory-of-mind areas in both populations to assess the impact of these changes in functional connectivity on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the theory-of-mind network (TPJp). Results SzP had pronounced decreases in connectivity in temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t(81)=4.4, p=0.00002). In HC the shortest path connecting visual and medial prefrontal theory-of-mind areas passed through TPJ-pSTS, whereas in SzP the shortest path passed through prefrontal cortex (PFC). While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r=0.43, p=0.002), it additionally correlated with connectivity along the PFC pathway only in SzP (rSzP=0.56, p=0.003). Conclusions These results suggest that connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal connectivity anomalies can have widespread impacts across cortex.

Background: Efficient processing of complex and dynamic social scenes relies on intact connectivity of many underlying cortical areas and networks, but how connectivity deficits affect this functioning in social cognition remains unknown. Here we measure these relationships using functionally based localization of social cognition areas, resting-state functional connectivity, and movie-watching data. Methods: In 42 schizophrenia participants (SzP) and 41 healthy controls (HC), we measured the functional connectivity of areas localized by face-emotion processing, theory-of-mind, and attention tasks. We quantified the weighted shortest path length between visual and medial prefrontal theory-of-mind areas in both populations to assess the impact of functional connectivity deficits on network structure. We then correlated connectivity along the shortest path in each group with movie-evoked activity in a key node of the theory-of-mind network (TPJp). Results: SzP had pronounced connectivity deficits in temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS) areas involved in face-emotion processing (t(81)=4.4, p=0.00002). In HC the shortest path connecting visual and medial prefrontal theory-of-mind areas passed through TPJ-pSTS, whereas in SzP the shortest path passed through prefrontal cortex (PFC). While movie-evoked TPJp activity correlated with connectivity along the TPJ-pSTS pathway in both groups (r=0.43, p=0.002), it additionally correlated with connectivity along the PFC pathway only in SzP (rSzP=0.56, p=0.003). Conclusions: Connectivity along the human-unique TPJ-pSTS pathway affects both the network architecture and functioning of areas involved in processing complex dynamic social scenes. These results demonstrate how focal deficits can have widespread impacts across cortex.

Schizophrenia is associated with marked impairments in social cognition. However, the neural correlates of these deficits remain unclear. Here we use naturalistic stimuli to examine the role of the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS)—an integrative hub for the cortical networks pertinent to the understanding complex social situations—in social inference, a key component of social cognition, in schizophrenia. 27 schizophrenia participants (SzP) and 21 healthy controls watched a clip of the movie “The Good, the Bad, and the Ugly” while high resolution multiband fMRI images were collected. We used inter-subject correlation (ISC) to measure the evoked activity, which we then compared to social cognition as measured by The Awareness of Social Inference Test (TASIT). We also compared between groups the TPJ-pSTS BOLD activity 1) relationship with the motion content in the movie, 2) synchronization with other cortical areas involved in the viewing of the movie, and 3) relationship with the frequency of saccades made during the movie. Activation deficits were greatest in middle TPJ (TPJm) and correlated significantly with impaired TASIT performance across groups. Follow-up analyses of the TPJ-pSTS revealed decreased synchronization with other cortical areas, decreased correlation with the motion content of the movie, and decreased correlation with the saccades made during the movie. The functional impairment of the TPJm, a hub area in the middle of the TPJ-pSTS, predicts deficits in social inference in SzP by disrupting the integration of visual motion processing into the TPJ. This disrupted integration then affects the use of the TPJ to guide saccades during the visual scanning of the movie clip. These findings suggest that the TPJ may be a treatment target for improving deficits in a key component of social cognition in SzP.

Background Impairments in social cognition contribute significantly to disability in schizophrenia patients (SzP). Perception of facial expressions is critical for social cognition. Intact perception requires an individual to visually scan a complex dynamic social scene for transiently moving facial expressions that may be relevant for understanding the scene. The relationship of visual scanning for these facial expressions and social cognition remains unknown. Methods In 39 SzP and 27 healthy controls (HC), we used eye-tracking to examine the relationship between performance on The Awareness of Social Inference Test (TASIT), which tests social cognition using naturalistic video clips of social situations, and visual scanning, measuring each individual's relative to the mean of HC. We then examined the relationship of visual scanning to the specific visual features (motion, contrast, luminance, faces) within the video clips. Results TASIT performance was significantly impaired in SzP for trials involving sarcasm ( p < 10 ⁻⁵ ). Visual scanning was significantly more variable in SzP than HC ( p < 10 ⁻⁶ ), and predicted TASIT performance in HC ( p = 0.02) but not SzP ( p = 0.91), differing significantly between groups ( p = 0.04). During the visual scanning, SzP were less likely to be viewing faces ( p = 0.0001) and less likely to saccade to facial motion in peripheral vision ( p = 0.008). Conclusions SzP show highly significant deficits in the use of visual scanning of naturalistic social scenes to inform social cognition. Alterations in visual scanning patterns may originate from impaired processing of facial motion within peripheral vision. Overall, these results highlight the utility of naturalistic stimuli in the study of social cognition deficits in schizophrenia.

The ability to search for and detect social cues, such as facial expressions of emotion, is critical to the understanding of complex dynamic social situations. This ability involves the coordinated actions of multiple cognitive domains, including face-emotion processing, mentalization, and visual attention. Individuals with schizophrenia are generally impaired in social cognition, and have been shown to have deficits in all of these domains. However, the whether the neural substrates of these impairments are shared or separate remains unclear. One candidate region for a shared substrate is the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS), which contains areas belonging to all of the cortical networks underlying these domains. Here we use functional MRI to examine differences in cortical activity evoked by a naturalistic movie, and link these results to impaired visual scanning and social cognition. 27 schizophrenia participants and 21 healthy controls watched a 15-minute clip of the movie "The Good, the Bad, and the Ugly" while high resolution multiband BOLD-fMRI activity was recorded. Inter-subject correlation was used to measure the evoked activity. BOLD-fMRI activity was also correlated with motion content in the movie, with the average activity in other cortical areas, and with frequency of saccades made during the movie. Visual scanning performance was measured in a separate behavioral experiment, and social cognition measured by The Awareness of Social Inference Test (TASIT). Contrasting the groups revealed that the TPJ-pSTS has the largest engagement deficit in both cortical hemispheres in schizophrenia patients versus healthy controls. Follow-up analyses find that brain activity in this region is less correlated with the motion content of the movie, that this region is abnormally synchronized to the other cortical areas involved in the cognitive domains underlying visual scanning of social scenes, and that activity this region is less correlated with the saccades made during the movie. Lastly, schizophrenia participant visual scanning performance of this clip was impaired compared to healthy controls, and correlated across the two groups with social cognition. These results indicate that the TPJ-pSTS plays less of an integral role in the coordination of face-emotion processing, mentalization, and visual attention in schizophrenia participants versus healthy controls. This functional deficit then impacts the visual scanning of a complex dynamic visual scenes, which in turn affects the comprehension of that scene. These findings indicating that the TPJ-pSTS is potentially the shared substrate for all of these deficits will lead to new treatments targeting this region to improve social cognition in individuals with schizophrenia.

The hippocampus exhibits striking volume reductions in schizophrenia (van Erp et al., 2016), with regionally specific changes in subfields cornu ammonis 1 to 4 (CA1-4), dentate gyrus, and subiculum (Mathew et al., 2014). Models of hippocampal function suggest an association with memory deficits in schizophrenia patients; for example, impairment of the pattern separation component of declarative memory in schizophrenia suggests dentate gyrus dysfunction (Das et al., 2014). As yet, however, there is incomplete understanding of how subfield structure contributes to these impairments. Relatedly, intrusions—a memory error where individuals mistakenly recall words from an incorrect list or never presented in any list—are associated with genetic risk for schizophrenia (Cannon et al., 2000), but hypothesized hippocampal pathophysiology remains unexplored. Childhood-onset schizophrenia, defined as onset before age 13, is a rare, possibly more homogenous, and severe form of the adult-onset disorder (Gochman et al., 2011). [...]

Background: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity. Methods: A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS. Results: Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P<0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on default-mode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P<0.05, corrected) for both patient groups. Conclusions: A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is state-related.

Objective: Working memory (WM) deficits are consistently reported in schizophrenia and are related to poor functional outcomes. Functional magnetic resonance imaging studies of adult-onset schizophrenia have reported decreased functional activations and connectivity in the WM network, but no prior functional magnetic resonance imaging study has examined WM in childhood-onset schizophrenia (COS). The aim of this study was to examine the neural correlates of WM in COS. Method: Adult patients with COS (n = 32, 21.3 ± 1.1 years), nonpsychotic siblings of patients with COS (n = 30, 19.4 ± 0.8 years), and healthy controls (n = 39, 20.0 ± 0.7 years) completed 1- and 2-back WM tasks during 3-T functional magnetic resonance imaging. Functional activation and connectivity analyses were conducted. A separate group of 23 younger patients with COS (17.9 ± 7.4 years) could not perform the tasks after twice completing a standard training and are not included in this report. Results: Patients with COS who were included scored significantly lower than controls on all tasks (p < .001). Patients with COS showed significantly lower activations in the dorsolateral prefrontal cortices, posterior parietal cortices, cerebellum, and caudate and decreased frontoparietal and corticostriatal functional connectivity compared with controls (p < .05, corrected). Siblings had functional activations and connectivity intermediate between those of patients and controls in a similar set of regions (p < .05, corrected). In patients, functional connectivity strength in the left frontoparietal network correlated positively with accuracy scores during the 1-back task (p = .0023, corrected). Conclusion: Decreased functional activation and connectivity in the WM network in COS supports pathophysiologic continuity with adult-onset schizophrenia. The low participation rate and accuracy of the patients highlights the disease severity of COS. Hypo-activations and hypo-connectivity were shared by siblings of patients with COS, suggesting COS as a potential endophenotype. Clinical trial registration information: Evaluating Genetic Risk Factors for Childhood-Onset Schizophrenia; http://ClinicalTrials.gov;NCT00001198.

Neurons within fMRI-defined face patches of the macaque brain exhibit shared categorical responses to flashed images but diverge in their responses under more natural viewing conditions. Here we investigate functional diversity among neurons in the anterior fundus (AF) face patch, combining whole-brain fMRI with longitudinal single-unit recordings in a local population (<1 mm³). For each cell, we computed a whole-brain correlation map based on its shared time course with voxels throughout the brain during naturalistic movie viewing. Based on this mapping, neighboring neurons showed markedly different affiliation with distant visually responsive areas and fell coarsely into subpopulations. Of these, only one subpopulation (∼16% of neurons) yielded similar correlation maps to the local fMRI signal. The results employ the readout of large-scale fMRI networks and, by indicating multiple functional domains within a single voxel, present a new view of functional diversity within a local neural population.