Carolina Bonivento

Attempts at memory control induce dysfunctional brain activation profiles in Generalized Anxiety Disorder: An exploratory fMRI study

Suppression of aversive memories through memory control has historically been proposed as a central psychological defense mechanism. Inability to suppress memories is considered a central psychological trait in several psychiatric disorders, including Generalized Anxiety Disorder (GAD). Yet, few studies have attempted the focused identification of dysfunctional brain activation profiles when patients with Generalized Anxiety Disorders attempt memory control. Using a well-characterized behavioral paradigm we studied brain activation profiles in a group of adult GAD patients and well-matched healthy controls (HC). Participants learned word-association pairs before imaging. During fMRI when presented with one word of the pair, they were instructed to either suppress memory of, or retrieve the paired word. Subsequent behavioral testing indicated both GAD and HC were able to engage in the task, but attempts at memory control (suppression or retrieval) during fMRI revealed vastly different activation profiles. GAD were characterized by substantive hypo-activation signatures during both types of memory control, with effects particularly strong during suppression in brain regions including the dorsal anterior cingulate and the ventral prefrontal cortex. Attempts at memory control in GAD fail to engage brain regions to the same extent HC, providing a putative neuronal signature for a well-established psychological characteristic of the illness.

Increased gyrification in schizophrenia and non affective first episode of psychosis

BACKGROUND Prefrontal cortex gyrification has been suggested to be altered in patients with schizophrenia and first episode psychosis. Therefore, it may represent a possible trait marker for these illnesses and an indirect evidence of a disrupted underlying connectivity. The aim of this study was to add further evidence to the existing literature on the role of prefrontal gyrification in psychosis by carrying out a study on a sizeable sample of chronic patients with schizophrenia and non-affective first-episode psychosis (FEP-NA) patients. METHODS Seventy-two patients with schizophrenia, 51 FEP-NA patients (12 who later develop schizophrenia) and 95 healthy controls (HC) underwent magnetic resonance imaging (MRI). Cortical folding was quantified using the automated gyrification index (GI). GI values were compared among groups and related to clinical variables. RESULTS Both FEP-NA and patients with schizophrenia showed a higher mean prefrontal GI compared to HC (all p<0.05). Interestingly, no differences have been observed between the two patients groups as well as between FEP-NA patients who did and did not develop schizophrenia. CONCLUSIONS Our results suggest the presence of a shared aberrant prefrontal GI in subjects with both schizophrenia and first-episode psychosis. These findings support the hypothesis that altered GI represents a neurodevelopmental trait marker for psychosis, which may be involved in the associated neurocognitive deficits.

T77. DIAGNOSTIC AND NEUROCOGNITIVE CORRELATES OF SCHIZOTYPY WITHIN AND ACROSS THE PRONIA STUDY GROUPS

Abstract Background Schizotypy traits range from odd behaviors to symptoms that resemble full schizophrenia, although less severe. Previous studies associated different degrees of positive and negative schizotypal traits to variations in the persons’ cognitive profiles while others related them to the risk to develop psychosis. We hypothesize that similar pattern of positive and negative schyzoypy traits characterize individuals at risk of psychosis and patients meeting the criteria for recent onset psychosis, although with different degrees of severity. Also, both should differ from depressed patients. Moreover, specific combinations of schizotypy traits and neurocognitive alterations should be associated to the different psychopathological profiles. The final goal of the study is to identify candidate predictors of risk of psychosis that will be used as features in next machine learning analyses. Methods The present is a multi-centric study that was conducted as part of the project titled ‘Personalised Prognostic Tools for Early Psychosis Management’ (PRONIA). 115 participants at high-risk for psychosis (CHR), 114 recent onset psychosis (ROP), 123 recent onset depression (ROD) and 252 healthy controls (HC) took part in the study. All were aged between 15 and 40 years. The participants filled the Wisconsin Schizotypy questionnaire, measuring positive (Magical Ideation Scale - MIS; Perceptual Aberration Scale - PAS) and negative schizotypy traits (Social Anhedonia Scale - SAnS; Physical Anhedonia Scale - PAnS). Moreover, they were administered the PRONIA Cognitive Battery (PCB), comprising measures of visuo-spatial dexterity and memory (Rey Figure, copy and delayed drawing), short-term memory (Digit Span - DS), Verbal Learning, Verbal Fluency, Attention (Continuous Performance Test - CPT, Digit Symbol Substitution Test - DSST), Emotions’ Recognition, General Intelligence (WAIS Vocabulary, Matrix Reasoning). Results We run i) a Multivariate Analysis of Covariance with ‘WSS subscales’ as dependent variable; ‘Group’ as between subject factor; ‘Age’ and ‘Gender’ as covariates; ii) a Multinomial logistic regression with ‘Group’ as dependent variable; HC ‘Group’ as reference parameter; ‘WSS subscales’ and scores at the PCB’s tests as predictors; ‘Age’ and ‘Gender’ as covariates. ROP and CHR reported both positive and negative schizotypy traits, although only the negative symptoms involving social aspects were clearly evident in CHR. Also, ROP and CHR differed for the positive symptoms, as they were present but at a lower level in CHR than in ROP. ROD instead scored high at the negative symptoms. Interestingly, ROP, CHR and ROD did not differ between each other for the negative symptoms, probably reflecting the effect of the psychopathology on the patients’ general motivation to life. The regressions analysis highlighted different patterns of associations of WSS and neurocognitive scores with the clinical status. In particular, the scores at the MIS, PAS and SanS combined with the Rey Figure (delayed drawing), predicted that the participants were CHR; the MIS, PAS and SAnS with measures of attention (CPT, DSST) predicted that the participant were ROP; the PAS; SAnS and short-term memory (DS) predicted to being ROD. Discussion Coherently with the hypotheses, different schizotypy traits or grade of severity characterized patients with distinct psychopathology profiles. Also, the association of WSS subscales with the cognitive measures differentiated between groups, with visuo-spatial long-term memory being associated to CHR, measures of attention relating to ROP and verbal short term memory relating to ROD. This makes these measures good candidates for the upcoming machine learning analyses.

T85. PRELIMINARY ANALYSES OF THE NEUROCOGNITIVE DATABASE OF PRONIA USING UNIVARIATE STATISTICS: CLINICAL GROUP DIFFERENCES

Abstract Background Neuro-cognitive deficits are a core feature of psychosis. In the clinical high risk stages of psychosis, neuro-cognitive deficits qualitatively affect the same functions while being quantitatively less marked compared to those in full-blown disorder. Therefore, cognitive impairments are considered to be an important intermediate phenotype for transition to psychosis. Partially overlapping deficits were also reported in depressive disorders, so it is important to identify deficits specifically associated to psychotic symptoms from those common to other conditions. We aimed to identify and differentiate cognitive deficits specifically associated to [i] psychopathology in general (i.e., presence of clinical diagnosis); [ii] psychotic symptoms; [iii] sub- and threshold levels of psychotic symptoms. Methods We compared four groups of participants within the project Personalised Prognostic Tools for Early Psychosis Management (PRONIA; www.pronia.eu). The PRONIA Cognitive Battery (PCB) includes 10 tests selected as reliable measures of neuropsychological difficulties in patients at high-risk of psychosis. The scores were obtained from the PRONIA Discovery Sample, which included 707 participants: 278 healthy controls (HC); 138 recent-onset depression (ROD); 139 clinical high-risk (CHR); 152 recent-onset psychosis (ROP), tested in seven sites across Europe. At first the norms were calculated correcting the HC’s raw scores by sex, age, cognitive level, education, and mother language (English, Finnish, German, Italian, or other). Then, univariate analyses of variance with a priori contrasts were used for directly comparing [i] HC vs ROD/CHR/ROP; [ii] ROD vs CHR/ROP; [iii] CHR vs ROP. Results The difference in cognitive performance between the clinical groups (ROD, CHR, ROP) as compared to the HC [i], was shown in measures of: speed of execution (ωP2 range 0.016–0.123; all p≤0.035); sustained attention (ωP2: 0.024–0.080; p≤0.022); verbal fluency (ωP2: 0.020–0.031; p≤0.002); emotion recognition (ωP2=0.026; p=0.001); visuo-spatial (ωP2: 0.018–0.049; p≤0.006) and verbal (ωP2: 0.038–0.075; p<0.001) both short- and long-term memory. Three clinical groups did not show significant difference in salience measures when compared with HC (p≥0.053), beyond a main effect of group (ωP2=0.015). Differences between ROD and CHR/ROP groups [ii] were detected in: speed of execution (all p≤0.001); sustained attention (p≤0.011); short-term and working memory (p≤0.004); long-term memory (p≤0.001); semantic verbal fluency (p=0.024); emotion recognition (p=0.005); and estimation of adaptive salience (p=0.021). When compared with ROP, CHR [iii] performed significantly better in the same domains that differentiated ROD from CHR/ROP, with the important exception of long-term memory measures (p≥0.094). Discussion These results are consistent with the expectations drawn from previous literature on the neuropsychological impairments in psychotic disorders and CHR participants. Furthermore, PCB showed to be useful in [i] psychopathology in general, [ii] differentiating between recent-onset depression and psychotic symptoms, and [iii] between threshold and sub-threshold psychotic symptoms. Interestingly, long-term memory deficits contributed more in differentiating psychotic symptoms from other psychopathological entities (ROD vs CHR/ROP comparison) than along the spectrum of attenuated psychotic symptoms, resulting in full clinical picture of psychosis (CHR vs ROP). Finally, salience attribution difficulties were confirmed to be associated with (sub-)threshold psychotic symptoms, more than to general psychopathology.

T137. CLASSIFICATION OF RECENT-ONSET PSYCHOSIS BASED ON RESTING-STATE FUNCTIONAL CONNECTIVITY AND THE RELATIONSHIP TO NEUROCOGNITIVE IMPAIRMENT

Abstract Background Impairments in cognitive functioning are a core feature of psychotic disorders and they have been associated with resting-state functional connectivity (rsFC) alterations in patients suffering from psychosis (Dauverman et al., 2014). Multivariate pattern analysis (MVPA) has proven to be a useful tool in the investigation of rsFC alteration in psychosis and in detecting subtle differences in multidimensional data sets (Kambeitz et al., 2015). In this study, we differentiated recent-onset psychosis patients (ROP) from healthy controls (HC) using a Support Vector Machine (SVM) classification based on rsFC. Furthermore, we investigated the relationship of the discriminative rsFC pattern to neurocognitive measures. Methods Resting-state fMRI and neurocognitive measures were obtained from 220 HC and 115 ROP across 7 sites of the PRONIA consortium. The rsFC matrix was estimated for each subject by calculating pairwise correlations between mean time series of 90 brain regions based on AAL parcellation. A L1-regularized L2-loss SVM was trained to classify ROP vs. HC based on rsFC in a repeated nested cross-validation. Decision scores for ROP were correlated with cognitive measures derived from the following neuropsychological tests: Rey Auditory Verbal Learning Task (RAVLT), Phonetic and Semantic Verbal Fluency, Diagnostic Analysis of Nonverbal Accuracy, Forward and Backward Digit Span, Self-ordered Pointing Task, and Salience Attribution Test. Results The classification algorithm was able to differentiate ROP and HC with a balanced accuracy (BAC) of 71.3% based on rsFC. The discriminative connectivity pattern included short-range connections between left putamen and left hippocampus, right putamen and right caudate nucleus, left superior frontal and right inferior orbitofrontal regions, as well as long-range connections between left and right occipital cortex and left cingulate gyrus, left supramarginal gyrus and right temporal pole. Two negative correlations between the SVM decision scores for ROP and measures of the RAVLT were significant (delayed recall: r=-0.3, Bonferroni –adjusted p<.04; recall after interference: r=-0.3, Bonferroni-adjusted p<.02). Discussion The classification performance was driven by a rsFC pattern including areas involved in memory processing, such as hippocampus and cingulate gyrus (Allen et al., 2007) as well as regions related to language processing, such as the supra marginal gyrus (Li et al., 2009). The negative correlation of rsFC-based decision scores with RAVLT measures shows that patients whose verbal learning and memory is more severely impaired exhibit a more distinctive rsFC pattern than patients with less impaired verbal memory.

Reduced cortical thickness and increased gyrification in generalized anxiety disorder: a 3 T MRI study

BACKGROUND Although the study of the neuroanatomical correlates of generalized anxiety disorder (GAD) is gaining increasing interest, up to now the cortical anatomy of GAD patients has been poorly investigated and still no data on cortical gyrification are available. The aim of the present study is to quantitatively examine the cortical morphology in patients with GAD compared with healthy controls (HC) using magnetic resonance imaging (MRI). To the best of our knowledge, this is the first study analyzing the gyrification patterns in GAD. METHODS A total of 31 GAD patients and 31 HC underwent 3 T structural MRI. For each subject, cortical surface area (CSA), cortical thickness (CT), gray matter volume (GMV), and local gyrification index (LGI) were estimated in 19 regions of interest using the Freesurfer software. These parameters were then compared between the two groups using General Linear Model designs. RESULTS Compared with HC, GAD patients showed: (1) reduced CT in right caudal middle frontal gyrus (p < 0.05, Bonferroni corrected), (2) hyper-gyrification in right fusiform, inferior temporal, superior parietal and supramarginal gyri and in left supramarginal and superior frontal gyri (p < 0.05, Bonferroni corrected). No significant alterations in CSA and GMV were observed. CONCLUSIONS Our findings support the hypothesis of a neuroanatomical basis for GAD, highlighting a possible key role of the right hemisphere. The alterations of CT and gyrification in GAD suggest a neurodevelopmental origin of the disorder. Further studies on GAD are needed to understand the evolution of the cerebral morphology with age and during the clinical course of the illness.

Temperament and Character Inventory in Bipolar Disorder versus Healthy Controls and Modulatory Effects of 3 Key Functional Gene Variants

Background: Bipolar disorder (BD) has been associated with temperamental and personality traits, although the relationship is still to be fully elucidated. Several studies investigated the genetic basis of temperament and character, identifying catechol-O-methyltransferase (COMT), brain derived neurotrophic factor (BDNF), and serotonin transporter (5-HTT) gene variants as strong candidates. Methods: In the GECO-BIP study, 125 BD patients and 173 HC were recruited. Subjects underwent to a detailed assessment and the temperament and character inventory 125 items (TCI) was administrated. Three functional genetic variants within key candidate genes (COMT rs4680, BDNF rs6265, and the serotonin-transporter-linked polymorphic region (5-HTTLPR)) were genotyped. Univariate and multivariate analyses were performed. Results: Compared to HC, BD patients showed higher scores in novelty seeking (NS; p = 0.001), harm avoidance (HA; p < 0.001), and self transcendence (St; p < 0.001), and lower scores in self directness (p < 0.001) and cooperativeness (p < 0.001) TCI dimensions. Concerning the genetic analyses, COMT rs4680 was associated with NS in the total sample (p = 0.007) and in the male subsample (p = 0.022). When performing the analysis in the HC and BD samples, the association was confirmed only in HC (p = 0.012), and in the HC male subgroup in particular (p = 0.004). BDNF rs6265 was associated with St in the BD group (p = 0.017). Conclusion: COMT rs4680 may modulate NS in males in the general population. This effect was not detected in BD patients, probably because BD alters the neurobiological basis of some TCI dimensions. BDNF rs6265 seems to modulate St TCI dimension only in BD patients, possibly modulating the previously reported association between rs6265 and BD treatment response. Further studies are needed to confirm our findings.

Deficit di regolazione emotiva in età evolutiva: analisi dei profili di funzionamento in un campione clinico italiano

Il processo di autoregolazione emotiva riveste un ambito d’interesse nello studio della psicopatologia, in particolare in eta evolutiva in quanto un deficit di auto-regolazione puo essere implicato sia in disturbi internalizzanti sia esternalizzanti. Alcuni ricercatori hanno operazionalizzato questo costrutto clinico utilizzando tre scale della CBCL -Child Behavior Check List per misurarlo: ansia/depressione, attenzione, comportamento aggressivo. Tali scale sono state utilizzate anche per identificare livelli piu severi di disregolazione emotiva che definiscono il Dysregulation Profile. Possibili outcome clinici sono stati individuati in difficolta nella regolazione dell’umore, nella gestione dei pensieri/preoccupazioni, nella regolazione del comportamento, nella regolazione cognitiva. In considerazione di queste premesse, il presente lavoro si pone l’obiettivo di studiare, in un campione clinico italiano di 1.224 soggetti in eta evolutiva, i livelli di disregolazione emotiva (CBCL-DESR e CBCL-DP) in funzione delle categorie di inquadramento diagnostico secondo DSM-IV. I risultati di questo studio esplorativo mostrano la presenza di pattern di disregolazione in un’ampia parte del campione clinico in esame, e di grave disregolazione soprattutto nei soggetti con quadro clinico piu grave.