Implicit socioemotional modulation of working memory brain activity in Schizophrenia 1, 2 Khalima A. Bolden, Ph.D., 3 Quintino Mano, Ph.D., 2 Michael Thomas, Ph.D., 2 Peter Wirth, B.S. 1, 2 Kristin S. Cadenhead, M.D., 1 Claire Murphy, Ph.D., 1 Elizabeth Twamley, Ph.D., 1 Ralph-Axel Mueller, Ph.D., 1, 2 Gregory G. Brown, Ph.D. SDSU/UCSD Joint Doctoral Program in Clinical Psychology, San Diego, CA 92182 VA Healthcare System, La Jolla, CA 92092 University of Cincinnati Department of Psychology, Cincinnati, OH 45221 BACKGROUND Social communication deficits, including Face-to-Face conversations, are a key feature of schizophrenia (Couture, Penn, & Roberts, 2006). Face-to-Face conversations involve reading the emotional tone of an individual’s facial and bodily expressions while tracking the verbal content of the conversation. Among other processes, successful conversations involve verbal working memory (WM) and face-emotion attribution. In previous research, we used a delayed match to sample task to study the behavioral correlates of implicit face processing as verbal WM load increased (See Methods for details). Our initial hypothesis was that the gradient of WM load on response time and error rate would be linear with greater slope following face primes than following geometric design primes. Instead we found a curvilinear relationship in two behavioral studies (Mano et al., 2014). AIMS Examine in controls the functional brain substrate of the disruptive effects of face primes at intermediate WM load and its inhibition at higher loads. Compare the functional neuroanatomy of the interaction of WM load with prime type found in controls with that found in schizophrenia patients. HYPOTHESES The BOLD signal contrast between Face and Geometric design conditions (FvG) will be a curvilinear function of WM load in the amygdala. The FvG contrast will be greatest at the highest WM load in the dorsolateral prefrontal cortex. The curvilinear pattern observed among controls in the amygdala will be altered in patients. RESULTS METHODS cont. PARTICIPANTS: Neuropsychological Information   IMAGE ACQUISITION GE MR 750 3.0 Tesla whole-body imaging system High-resolution Structural Scan: T1-weighted (T1w) (NEX = 1, TI = 450 ms, TE= minimum full, flip angle = 12o, receiver bandwidth = 31.25 kHz, 256 x 256 matrix, Field of View = 220 mm, in-plane resolution = 0.859 mm x 0.859 mm, 166 interleaved sagittal slices thickness=1.2 mm). We acquired four runs of the Implicit Facial-Affect and Working Memory Paradigm. Each of the four versions of the WM task lasted 9.7 minutes and possessed the same general structure as shown below. Pseudowords were to be briefly retained with WM load manipulated by altering the number of syllables (1, 2, 3) in each pseudoword (McKenna et al. 2013). Thirty-two single shot, non-oblique, echoplanar 4 mm axial covering the whole brain were acquired using a gradient echo protocol (fat saturation TR=2000 ms, TE=30 ms, flip angle = 77o, image matrix = 64 X 64, Field of View = 240 mm, 3.75 mm X 3.75 mm in-plane resolution, 291 time points) for each of four runs IMAGE & STATISTICAL ANALYSIS Preprocessing done to remove artifacts and move images into a standardized (Talairach) space. Regions of Interest (DLPFC and Amygdala) defined using AFNI Talairach Daemon (see below). General linear model (GLM) used to generate the amplitude of the BOLD response for each study effect. Repeated Measures ANOVA of 4 (run) x 3 (WM memory load) x 2 (hemisphere) analyses performed for each group. FvG contrast was tested using orthogonal linear and quadratic contrasts for each ROI: 2 (control vs. patient) by 3 (memory load) by 2 (hemisphere) analysis of variance Syllable Effect on Face vs Geometric Design Contrast (FvG)in Amgydala ** ** Controls Patients BOLD Response to Face or Design Stimuli Contrasted with the Implied Baseline Effect of WM manipulation on the FvG contrast in the Amygdala during maintenance period: Controls: Significant quadratic effect in the right hemisphere of WM load on the FvG contrast [BOLD response to designs > faces at intermediate load] in the direction opposite to that hypothesized (F[1,19] = 10.423, p = .004, MSE = .121, 2 = .35). Patients: Significant quadratic effect in the right hemisphere of WM load on the FvG contrast [BOLD response to faces > designs at intermediate load] in the direction hypothesized but opposite to the direction of the control finding (F[1,11] = 10.442 p = .008, 2 = .49). Syllable Effect on Face & Design Stimuli Activation in Dorsolateral Prefrontal Cortex Percent signal change of the FvG contrast in the DLPFC during maintenance: Controls: Significant linear effect of WM load on the FvG contrast in the direction compatible with the hypothesis (F[1,19] = 5.818, p = .026, MSE = .077, 2 = .23). Patients: A quadratic effect of WM load on the FvG contrast significant only in the right hemisphere (F[1,11] = 9.362, p = .011, 2 = .40). METHODS PARTICIPANTS 20 healthy controls similar in mean age and gender distribution to schizophrenia patients. 12 participants who were diagnosed with schizophrenia or schizoaffective disorder. Demographic Information Neuropsychological Functioning FINDINGS We based the study hypotheses on a distraction-suppression hypothesis: Face primes would produce a greater BOLD response in the maintenance period compared with geometric designs. This face prime effect would be suppressed at the highest working memory load producing a curvilinear BOLD response to WM load in the amygdala and a linear response in the DLPFC. The BOLD response following face primes compared with geometric design primes was a curvilinear function of working memory load but the direction of the effect was in the predicted direction only in the right hemisphere of schizophrenia group. The BOLD response following face distraction compared with geometric design distraction was a linear function of WM load but only in the controls. The BOLD response to the geometric designs was not constant across WM load and substantially contributed to the face prime vs. geometric prime contrast of interest.   Controls Patients Effect Size Hedges g Age 39.37 (±10.1) 40 (±8.4) -0.07 Education ** 15.58 (±1.62) 13.38 (±1.5) 1.40 Maternal Education 13.83 (±3.1) 11.75 (±4.5) 0.55 Paternal Education 14.1 (±3.1) 13.5 (±3.3) 0.64 Maternal Income $30,210.5 (±28,359) $20,090 (±24,002) 0.38 Paternal Income $74,447.4 (±105,207) $49,780 (±48,336) 0.28 BAI** 1.71 (± 2.78) 8.42 (±7.50)  -1.33 BDI** 2.64 (±4.72) 9.25 (±10.54)  -0.89 PANSS Positive ----- 13.33 (3.985) PANSS Negative 17 (4.178) PANSS General 26.17 (8.83) Age at first hospitalization 18.38 (7.891) Age at first diagnosis 20.2 (7.757) Number of hospitalizations 3.36 (2.767) References Regions of Interest Prefrontal areas Amygdala Couture, S. M., Penn, D. L., & Roberts, D. L. (2006). The Functional Significance of Social Cognition in Schizophrenia: A Review. Schizophrenia Bulletin, 32(suppl 1), S44-S63. doi: 10.1093/schbul/sbl029 Mano, Q. R., Brown, G. G., Mirzakhanian, H., Bolden, K., Cadenhead, K. S., & Light, G. A. (2014). Not all distraction is bad: working memory vulnerability to implicit socioemotional distraction correlates with negative symptoms and functional impairment in psychosis. Schizophrenia Research Treatment, 2014, 320948. doi: 10.1155/2014/320948 McKenna BS, Brown GG, Drummond SP, Turner TH, Mano QR. (2013). Linking mathematical modeling with human neuroimaging to segregate verbal working memory maintenance processes from stimulus encoding. Neuropsychology. 2013 Mar;27(2):243-55. doi: 10.1037/a0031515. PubMed PMID: 23527652.