Fabio Bernardoni

Correspondence of DNA Methylation Between Blood and Brain Tissue and its Application to Schizophrenia Research

Given the difficulty of procuring human brain tissue, a key question in molecular psychiatry concerns the extent to which epigenetic signatures measured in more accessible tissues such as blood can serve as a surrogate marker for the brain. Here, we aimed (1) to investigate the blood-brain correspondence of DNA methylation using a within-subject design and (2) to identify changes in DNA methylation of brain-related biological pathways in schizophrenia.We obtained paired blood and temporal lobe biopsy samples simultaneously from 12 epilepsy patients during neurosurgical treatment. Using the Infinium 450K methylation array we calculated similarity of blood and brain DNA methylation for each individual separately. We applied our findings by performing gene set enrichment analyses (GSEA) of peripheral blood DNA methylation data (Infinium 27K) of 111 schizophrenia patients and 122 healthy controls and included only Cytosine-phosphate-Guanine (CpG) sites that were significantly correlated across tissues.Only 7.9% of CpG sites showed a statistically significant, large correlation between blood and brain tissue, a proportion that although small was significantly greater than predicted by chance. GSEA analysis of schizophrenia data revealed altered methylation profiles in pathways related to precursor metabolites and signaling peptides.Our findings indicate that most DNA methylation markers in peripheral blood do not reliably predict brain DNA methylation status. However, a subset of peripheral data may proxy methylation status of brain tissue. Restricting the analysis to these markers can identify meaningful epigenetic differences in schizophrenia and potentially other brain disorders.

Weight restoration therapy rapidly reverses cortical thinning in anorexia nervosa: A longitudinal study.

Structural magnetic resonance imaging studies have documented reduced gray matter in acutely ill patients with anorexia nervosa to be at least partially reversible following weight restoration. However, few longitudinal studies exist and the underlying mechanisms of these structural changes are elusive. In particular, the relative speed and completeness of brain structure normalization during realimentation remain unknown. Here we report from a structural neuroimaging study including a sample of adolescent/young adult female patients with acute anorexia nervosa (n=47), long-term recovered patients (n=34), and healthy controls (n=75). The majority of acutely ill patients were scanned longitudinally (n=35): at the beginning of standardized weight restoration therapy and again after partial weight normalization (>10% body mass index increase). High-resolution structural images were processed and analyzed with the longitudinal stream of FreeSurfer software to test for changes in cortical thickness and volumes of select subcortical regions of interest. We found globally reduced cortical thickness in acutely ill patients to increase rapidly (0.06 mm/month) during brief weight restoration therapy (≈3 months). This significant increase was predicted by weight restoration alone and could not be ascribed to potentially mediating factors such as duration of illness, hydration status, or symptom improvements. By comparing cortical thickness in partially weight-restored patients with that measured in healthy controls, we confirmed that cortical thickness had normalized already at follow-up. This pattern of thinning in illness and rapid normalization during weight rehabilitation was largely mirrored in subcortical volumes. Together, our findings indicate that structural brain insults inflicted by starvation in anorexia nervosa may be reversed at a rate much faster than previously thought if interventions are successful before the disorder becomes chronic. This provides evidence drawing previously speculated mechanisms such as (de-)hydration and neurogenesis into question and suggests that neuronal and/or glial remodeling including changes in macromolecular content may underlie the gray matter alterations observed in anorexia nervosa.

Preserved white matter microstructure in young patients with anorexia nervosa

A massive but reversible reduction of cortical thickness and subcortical gray matter (GM) volumes in Anorexia Nervosa (AN) has been recently reported. However, the literature on alterations in white matter (WM) volume and microstructure changes in both acutely underweight AN (acAN) and after recovery (recAN) is sparse and results are inconclusive. Here, T1‐weighted and diffusion‐weighted MRI data in a sizable sample of young and medication‐free acAN (n = 35), recAN (n = 32), and age‐matched female healthy controls (HC, n = 62) were obtained. For analysis, a well‐validated global probabilistic tractography reconstruction algorithm including rigorous motion correction implemented in FreeSurfer: TRACULA (TRActs Constrained by UnderLying Anatomy) were used. Additionally, a clustering algorithm and a multivariate pattern classification technique to WM metrics to predict group membership were applied. No group differences in either WM volume or WM microstructure were detected with standard analysis procedures either in acAN or recAN relative to HC after controlling for the number of performed statistical tests. These findings were not affected by age, IQ, or psychiatric symptoms. While cluster analysis was unsuccessful at discriminating between groups, multivariate pattern classification showed some ability to separate acAN from HC (but not recAN from HC). However, these results were not compatible with a straightforward hypothesis of impaired WM microstructure. The current findings suggest that WM integrity is largely preserved in non‐chronic AN. This finding stands in contrast to findings in GM, but may help to explain the relatively intact cognitive performance of young patients with AN and provide the basis for the fast recovery of GM structures. Hum Brain Mapp 37:4069–4083, 2016.

Continuum limit of the leading-order HQET form factor in Bs→Kℓν decays

Abstract We discuss the computation of form factors for semi-leptonic decays of B-, B s -mesons in lattice QCD. Considering in particular the example of the static B s form factors we demonstrate that after non-perturbative renormalization the continuum limit can be taken with confidence. The resulting precision is of interest for extractions of V ub . The size of the corrections of order 1 / m b is just estimated at present but it is expected that their inclusion does not pose significant difficulties.

Increased anterior cingulate cortex response precedes behavioural adaptation in anorexia nervosa

Patients with anorexia nervosa (AN) are characterised by increased self-control, cognitive rigidity and impairments in set-shifting, but the underlying neural mechanisms are poorly understood. Here we used functional magnetic resonance imaging (fMRI) to elucidate the neural correlates of behavioural adaptation to changes in reward contingencies in young acutely ill AN patients. Thirty-six adolescent/young adult, non-chronic female AN patients and 36 age-matched healthy females completed a well-established probabilistic reversal learning task during fMRI. We analysed hemodynamic responses in empirically-defined regions of interest during positive feedback and negative feedback not followed/followed by behavioural adaptation and conducted functional connectivity analyses. Although overall task performance was comparable between groups, AN showed increased shifting after receiving negative feedback (lose-shift behaviour) and altered dorsal anterior cingulate cortex (dACC) responses as a function of feedback. Specifically, patients had increased dACC responses (which correlated with perfectionism) and task-related coupling with amygdala preceding behavioural adaption. Given the generally preserved task performance in young AN, elevated dACC responses specifically during behavioural adaption is suggestive of increased monitoring for the need to adjust performance strategies. Higher dACC-amygdala coupling and increased adaptation after negative feedback underlines this interpretation and could be related to intolerance of uncertainty which has been suggested for AN.

Neural correlates of altered feedback learning in women recovered from anorexia nervosa

Anorexia nervosa (AN) is associated with exaggerated self-control and altered reward-based decision making, but the underlying neural mechanisms are poorly understood. Consistent with the notion of excessive cognitive control, we recently found increased dorsal anterior cingulate cortex (dACC) activation in acutely ill patients (acAN) on lose-shift trials in a probabilistic reversal learning (PRL) task. However, undernutrition may modulate brain function. In attempt to disentangle trait from state factors, the current fMRI study investigated cognitive control in recovered patients (recAN). Thirty-one recAN and 31 healthy controls (HC) completed a PRL task during fMRI. Based on previous findings, we focused on hemodynamic responses during lose-shift behaviour and conducted supplementary functional connectivity analysis. RecAN showed elevated lose-shift behaviour relative to HC. On the neural level, recAN showed normal dACC responses, but increased activation in fronto-parietal control regions. A trend for increased coupling between frontal and parietal regions of interest was also evident in recAN. The current findings in recAN differ from those in our previous study in acAN. While aberrant dACC response to negative feedback may be a correlate of the underweight state in acAN, impaired behavioural adaptation and elevated activation of cognitive control regions in recAN is suggestive of altered neural efficiency.

Altered Medial Frontal Feedback Learning Signals in Anorexia Nervosa

BACKGROUND In their relentless pursuit of thinness, individuals with anorexia nervosa (AN) engage in maladaptive behaviors (restrictive food choices and overexercising) that may originate in altered decision making and learning. METHODS In this functional magnetic resonance imaging study, we employed computational modeling to elucidate the neural correlates of feedback learning and value-based decision making in 36 female patients with AN and 36 age-matched healthy volunteers (12-24 years). Participants performed a decision task that required adaptation to changing reward contingencies. Data were analyzed within a hierarchical Gaussian filter model that captures interindividual variability in learning under uncertainty. RESULTS Behaviorally, patients displayed an increased learning rate specifically after punishments. At the neural level, hemodynamic correlates for the learning rate, expected value, and prediction error did not differ between the groups. However, activity in the posterior medial frontal cortex was elevated in AN following punishment. CONCLUSIONS Our findings suggest that the neural underpinning of feedback learning is selectively altered for punishment in AN.

The real-life costs of emotion regulation in anorexia nervosa: a combined ecological momentary assessment and fMRI study

Regulation of emotions is necessary for successful attainment of short-term and long-term goals. However, over-regulation may also have its costs. In anorexia nervosa (AN), forgoing food intake despite emaciation and endocrine signals that promote eating is an example of “too much” self-control. Here we investigated whether voluntary emotion regulation in AN patients comes with associated disorder-relevant costs. Thirty-five patients with acute AN and thirty-five age-matched healthy controls (HCs) performed an established emotion regulation paradigm during functional magnetic resonance imaging after an overnight fast. The task required reducing emotions induced by positively valenced pictures via distancing. We calculated a neural regulation score from responses recorded in a reward-related brain region of interest (ventral striatum; VS) by subtracting activation measured on “positive distance” trials from that elicited under the “positive watch” (baseline) condition. Complementing the imaging data, we used ecological momentary assessment (EMA) to probe disorder-related rumination and affect six times/day for 2 weeks following the scanning session. The neural regulation score indicating reduced VS activation during emotion regulation was used as a predictor in hierarchical linear models with EMA measures as outcomes. No group differences in neural activity were found for the main contrasts of the task. However, regulation of VS activity was associated with increased body-related rumination and increased negative affect in AN, but not in HC. In line with this finding, correlational analysis with longitudinal BMI measurements revealed a link between greater VS regulation and poorer treatment outcome after 60 and 90 days. Together, these results identify a neural correlate of altered emotion regulation in AN, which seems to be detrimental to psychological well-being and may interfere with recovery.

Processing and regulation of negative emotions in anorexia nervosa: An fMRI study

Theoretical models and recent advances in the treatment of anorexia nervosa (AN) have increasingly focused on the role of alterations in the processing and regulation of emotions. To date, however, our understanding of these changes is still limited and reports of emotional dysregulation in AN have been based largely on self-report data, and there is a relative lack of objective experimental evidence or neurobiological data. The current functional magnetic resonance imaging (fMRI) study investigated the hemodynamic correlates of passive viewing and voluntary downregulation of negative emotions by means of the reappraisal strategy detachment in AN patients. Detachment is regarded as adaptive regulation strategy associated with a reduction in emotion-related amygdala activity and increased recruitment of prefrontal brain regions associated with cognitive control processes. Emotion regulation efficacy was assessed via behavioral arousal ratings and fMRI activation elicited by an established experimental paradigm including negative images. Participants were instructed to either simply view emotional pictures or detach themselves from feelings triggered by the stimuli. The sample consisted of 36 predominantly adolescent female AN patients and a pairwise age-matched healthy control group. Behavioral and neuroimaging data analyses indicated a reduction of arousal and amygdala activity during the regulation condition for both patients and controls. However, compared with controls, individuals with AN showed increased activation in the amygdala as well as in the right dorsolateral prefrontal cortex (dlPFC) during the passive viewing of aversive compared with neutral pictures. These results extend previous findings indicative of altered processing of salient emotional stimuli in AN, but do not point to a general deficit in the voluntary regulation of negative emotions. Increased dlPFC activation in AN during passive viewing of negative stimuli is in line with the hypothesis that the disorder may be characterized by excessive self-control. Taken together, the data seem to suggest that reappraisal via detachment may be an effective strategy to reduce negative arousal for individuals with AN.