Comparing feature selection and machine learning approaches for predicting CYP2D6 methylation from genetic variation.

Introduction: Pharmacogenetics currently supports clinical decision-making on the basis of a limited number of variants in a few genes and may benefit paediatric prescribing where there is a need for more precise dosing. Integrating genomic information such as methylation into pharmacogenetic models holds the potential to improve their accuracy and consequently prescribing decisions. Cytochrome P450 2D6 (CYP2D6) is a highly polymorphic gene conventionally associated with the metabolism of commonly used drugs and endogenous substrates. We thus sought to predict epigenetic loci from single nucleotide polymorphisms (SNPs) related to CYP2D6 in children from the GUSTO cohort. Methods: Buffy coat DNA methylation was quantified using the Illumina Infinium Methylation EPIC beadchip. CpG sites associated with CYP2D6 were used as outcome variables in Linear Regression, Elastic Net and XGBoost models. We compared feature selection of SNPs from GWAS mQTLs, GTEx eQTLs and SNPs within 2 MB of the CYP2D6 gene and the impact of adding demographic data. The samples were split into training (75%) sets and test (25%) sets for validation. In Elastic Net model and XGBoost models, optimal hyperparameter search was done using 10-fold cross validation. Root Mean Square Error and R-squared values were obtained to investigate each models' performance. When GWAS was performed to determine SNPs associated with CpG sites, a total of 15 SNPs were identified where several SNPs appeared to influence multiple CpG sites. Results: Overall, Elastic Net models of genetic features appeared to perform marginally better than heritability estimates and substantially better than Linear Regression and XGBoost models. The addition of nongenetic features appeared to improve performance for some but not all feature sets and probes. The best feature set and Machine Learning (ML) approach differed substantially between CpG sites and a number of top variables were identified for each model. Discussion: The development of SNP-based prediction models for CYP2D6 CpG methylation in Singaporean children of varying ethnicities in this study has clinical application. With further validation, they may add to the set of tools available to improve precision medicine and pharmacogenetics-based dosing.

Transdiagnostic clustering of self-schema from self-referential judgements identifies subtypes of healthy personality and depression.

Introduction: The heterogeneity of depressive and anxiety disorders complicates clinical management as it may account for differences in trajectory and treatment response. Self-schemas, which can be determined by Self-Referential Judgements (SRJs), are heterogeneous yet stable. SRJs have been used to characterize personality in the general population and shown to be prognostic in depressive and anxiety disorders. Methods: In this study, we used SRJs from a Self-Referential Encoding Task (SRET) to identify clusters from a clinical sample of 119 patients recruited from the Institute of Mental Health presenting with depressive or anxiety symptoms and a non-clinical sample of 115 healthy adults. The generated clusters were examined in terms of most endorsed words, cross-sample correspondence, association with depressive symptoms and the Depressive Experiences Questionnaire and diagnostic category. Results: We identify a 5-cluster solution in each sample and a 7-cluster solution in the combined sample. When perturbed, metrics such as optimum cluster number, criterion value, likelihood, DBI and CHI remained stable and cluster centers appeared stable when using BIC or ICL as criteria. Top endorsed words in clusters were meaningful across theoretical frameworks from personality, psychodynamic concepts of relatedness and self-definition, and valence in self-referential processing. The clinical clusters were labeled "Neurotic" (C1), "Extraverted" (C2), "Anxious to please" (C3), "Self-critical" (C4), "Conscientious" (C5). The non-clinical clusters were labeled "Self-confident" (N1), "Low endorsement" (N2), "Non-neurotic" (N3), "Neurotic" (N4), "High endorsement" (N5). The combined clusters were labeled "Self-confident" (NC1), "Externalising" (NC2), "Neurotic" (NC3), "Secure" (NC4), "Low endorsement" (NC5), "High endorsement" (NC6), "Self-critical" (NC7). Cluster differences were observed in endorsement of positive and negative words, latency biases, recall biases, depressive symptoms, frequency of depressive disorders and self-criticism. Discussion: Overall, clusters endorsing more negative words tended to endorse fewer positive words, showed more negative biases in reaction time and negative recall bias, reported more severe depressive symptoms and a higher frequency of depressive disorders and more self-criticism in the clinical population. SRJ-based clustering represents a novel transdiagnostic framework for subgrouping patients with depressive and anxiety symptoms that may support the future translation of the science of self-referential processing, personality and psychodynamic concepts of self-definition to clinical applications.

Positive mental health in psychotherapy: a qualitative study from psychotherapists' perspectives.

BACKGROUND: There is growing evidence in the literature on the use of positive mental health (PMH) interventions among clinical samples. This qualitative study aims to explore the definitions of PMH from psychotherapists' perspectives, and to examine views and attitudes related to the construct. METHODS: Focus group discussions were conducted with psychotherapists at a tertiary psychiatric institute. Focus group sessions were transcribed verbatim and transcripts were analyzed using an inductive thematic approach. RESULTS: Five themes related to psychotherapists' definition of PMH were identified: (1) acceptance; (2) normal functioning and thriving in life; (3) resilience; (4) positive overall evaluation of life; (5) absence of negative emotions and presence of positive emotion states. Themes related to views and attitudes towards PMH were: (1) novel and valuable for psychotherapy; (2) reservations with terminology; (3) factors influencing PMH. CONCLUSION: PMH in psychotherapy is a multidimensional concept that means more than symptom management and distress reduction in clients. There is potential value for its application in psychotherapy practice, though some concerns need to be addressed before it can be well integrated.

COVID-19-Related Life Experiences, Outdoor Play, and Long-term Adiposity Changes Among Preschool- and School-Aged Children in Singapore 1 Year After Lockdown.

IMPORTANCE: Despite the potential for COVID-19 infection control-related events to have an effect on child well-being, comprehensive assessments of postlockdown changes and persistent outcomes are lacking. OBJECTIVE: To survey the extent of COVID-19 lockdown-related lifestyle changes, their differences by child age and family socioeconomic status, and the potential association with child adiposity 1 year after lockdown. DESIGN, SETTING, AND PARTICIPANTS: A self-administered, electronic survey was introduced to 2 ongoing child cohorts (the Singapore Preconception Study of Long-term Maternal and Child Outcomes [S-PRESTO] cohort of preschool children aged 1-4.5 years and the Growing Up in Singapore Towards Healthy Outcomes [GUSTO] cohort of primary school children aged 9-10.7 years) from July 8, 2020, to September 5, 2020, which was 1 to 3 months after the end of strict universal movement restrictions (duration of 73 days ending on June 19, 2020). All active participants from S-PRESTO and GUSTO, 2 population-based, longitudinal, parent-offspring cohorts in Singapore, were invited to participate and monitored through June 15, 2021. EXPOSURES: Exposures included family income before and after the COVID-19 lockdown, changes in child outdoor play or exercise, and COVID-19-related life events; all data were self-reported by parents and school-aged children 1 to 3 months after the lockdown. MAIN OUTCOMES AND MEASURES: Primary outcomes were self-reported COVID-19-related life events and changes in child online socialization, outdoor play or exercise, and intrafamily relationships. Study staff measured children's weight, height, and skinfold thickness before and up to 1 year after lockdown. Body mass indices (calculated as weight in kilograms divided by height in meters squared) and World Health Organization-standardized scores were computed. Differences before and after lockdown were compared using baseline-adjusted linear regression. RESULTS: A total of 604 parents (53% of active cohort participants) and 356 school-aged children completed the survey and were similar to source cohorts. This represents 373 of 761 eligible children in the GUSTO cohort (mean [SD] age, 9.9 [0.4] years; 197 girls [52.8%]) and 231 of 370 eligible children in the S-PRESTO cohort (mean [SD] age, 2.6 [0.8] years; 121 boys [52.6%]). The COVID-19-related life changes were prevalent and varied (eg, 414 of 600 children [69.0%] reported changes in social activities). More than one-third of primary school-aged children (122 of 356 [34.3%]) and one-quarter of preschool-aged children (56 of 229 [24.5%]) eliminated any outdoor play after the lockdown. Lower family income before the lockdown was associated with increased odds of elimination of outdoor play (adjusted odds ratio per 1000 Singapore dollars [$730 US dollars] decrease, 1.09; 95% CI, 1.01-1.19). Complete elimination of outdoor activity (vs continued outdoor activity) was associated with an increase in body mass index of 0.48 (95% CI, 0.03-0.94) and a body mass index z score of 0.18 units (95% CI, 0-0.37) in school-aged children approximately 1 year after lockdown. CONCLUSIONS AND RELEVANCE: Results of this cohort study suggest that 1 to 3 months after a brief, strict lockdown, a large proportion of parents and school-aged children reported elimination of outdoor play, which was more prevalent in lower-income families. Future research to better understand clinical implications and ways to mitigate lockdown outcomes is essential.

"We Are All Trying to Find a Way to Help Ourselves": A Look at Self-Help Strategies Among Psychotherapy Clients.

Objective: This study examined self-help strategies engaged by psychotherapy clients and explored their views on such self-help approach. Methods: Secondary analysis of data from a qualitative research study was conducted. A total of 15 psychotherapy clients were recruited, and data were collected via semi-structured interviews. Thematic analysis of data was conducted using inductive approach to examine the content. Results: Three main themes revolving around self-help strategies were identified: (1) types of self-help strategies, (2) reasons for engaging in self-help activities, and (3) effectiveness of self-help strategies. Conclusion: The self-help approach to manage distress is common among psychotherapy clients. This study provided insights into understanding how and why clients use self-help strategies in their daily lives.

Effect of aripiprazole as an adjunct to atypical antipsychotics on weight and metabolic profile: a 12-week open-label trial.

BACKGROUND: Atypical antipsychotics are widely prescribed, yet have been associated with weight gain and metabolic syndrome. AIM: To study the effect of adjunct low-dose aripiprazole on weight and metabolic parameters of subjects on atypical antipsychotics (olanzapine, clozapine or risperidone). METHODS: The study was carried out as an open-label trial with a fixed dose of 5 mg aripiprazole added to the patient's current antipsychotic for 12 weeks. The primary outcome measure was mean change in weight, while secondary outcome measures included change in waist circumference; fasting blood glucose; HbA1c; triglycerides; total, HDL and LDL cholesterol levels; functioning; and neurocognition. RESULTS: For the overall study (n = 55), there was no significant effect of adjunct aripiprazole on the weight of the subjects. However, the clozapine group achieved significant weight loss (p = 0.002) and also had significant improvements in total cholesterol (p < 0.001), HDL (p = 0.016), LDL (p = 0.044) and triglyceride levels (p = 0.038). The olanzapine group had significant improvement in triglycerides (p = 0.001), and other metabolic parameters for this group showed improvement trends, but did not reach statistical significance. The risperidone group did not show any significant improvement in weight or metabolic parameters. CONCLUSIONS: The study adds support to the adjunctive use of aripiprazole to clozapine for weight loss and improvement in metabolic profile, and for reduction in cardiometabolic risk for patients on olanzapine. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02949752.

A Randomised Controlled Trial of Clinician-Guided Internet-Based Cognitive Behavioural Therapy for Depressed Patients in Singapore.

This study examined the efficacy and acceptability of a hybrid, clinician-guided internet-based Cognitive Behavioural Therapy (iCBT) programme for outpatients with depression in a psychiatric hospital in Singapore. Fifty three participants were randomly assigned to a treatment or wait-list control group before they underwent a cross-over of conditions. Treatment consisted of a 4-week iCBT with three face-to-face sessions. 60.9% of participants who received treatment completed all six modules. Intention-to-treat analysis showed treatment was associated with significant reductions in symptoms of depression, anxiety and psychological distress but not in functional impairment, while the control condition was not associated with changes in any measures. These reductions had moderate to large effect sizes (ESs) for symptoms of depression and anxiety, and moderate ES for psychological distress. The between-group difference in depression score had a moderate ES. There was a significant between-group treatment effect in depressive symptoms, but not in the other measures. Treatment gains were maintained at 3-month follow-up. Most of the participants were highly satisfied with the programme, with 90 percent stating they would recommend it. This is the first RCT to provide preliminary evidence for the efficacy and acceptability of iCBT for depression in Singapore.

The influence of microsatellite polymorphisms in sex steroid receptor genes ESR1, ESR2 and AR on sex differences in brain structure.

The androgen receptor (AR), oestrogen receptor alpha (ESR1) and oestrogen receptor beta (ESR2) play essential roles in mediating the effect of sex hormones on sex differences in the brain. Using Voxel-based morphometry (VBM) and gene sizing in two independent samples (discovery n â€‹= â€‹173, replication â€‹= â€‹61), we determine the common and unique influences on brain sex differences in grey (GM) and white matter (WM) volume between repeat lengths (n) of microsatellite polymorphisms AR(CAG)n, ESR1(TA)n and ESR2(CA)n. In the hypothalamus, temporal lobes, anterior cingulate cortex, posterior insula and prefrontal cortex, we find increased GM volume with increasing AR(CAG)n across sexes, decreasing ESR1(TA)n across sexes and decreasing ESR2(CA)n in females. Uniquely, AR(CAG)n was positively associated with dorsolateral prefrontal and orbitofrontal GM volume and the anterior corona radiata, left superior fronto-occipital fasciculus, thalamus and internal capsule WM volume. ESR1(TA)n was negatively associated with the left superior corona radiata, left cingulum and left inferior longitudinal fasciculus WM volume uniquely. ESR2(CA)n was negatively associated with right fusiform and posterior cingulate cortex uniquely. We thus describe the neuroanatomical correlates of three microsatellite polymorphisms of steroid hormone receptors and their relationship to sex differences.

Strategies to analyse data obtained from liquid intrusion experiments of loose porous materials.

Liquid intrusion remains one of the most common methods to measure the contact angle of liquids to powders. However, as there are two unknown variables in the Washburn equation: the material constant (that is, the pore structure of the powder bed) and the contact angle of the liquid to the powder, this method requires the use of two liquids-a liquid of interest (the probe liquid) and a reference liquid. The reference liquid should, ideally, make a contact angle of 0° to the sample. However, in practice a low surface tension liquid is normally selected. This paper proposes a more standardised approach for the selection of the reference liquid based on experimental data. Additionally, a major assumption of the liquid intrusion method is that the pore structure, as measured by the material constant, C, is identical for all powder beds (provided that the same packing procedure is used for the same samples). In real systems, however, this is an approximation, and not likely to hold strictly true. Therefore, difficulties may arise with data analysis as there is a potential uncertainty in the most appropriate order to divide the gradient of the probe liquid by the gradient of the reference liquid. This paper proposes three specific methods of analysing such data, each with their own advantages and limitations. Hence, the selection of which method should be used is criteria-based, assessed on the basis of the obtained data.

Applying surface energy derived cohesive-adhesive balance model in predicting the mixing, flow and compaction behaviour of interactive mixtures.

OBJECTIVE: In this study, we investigated the applicability of cohesive-adhesive balance (CAB) model to predict the interactive mixing behaviour of small excipient particles. Further, we also investigated the application of this CAB model to predict the flow and compactibility of resultant blends. METHODS: Excipients created by co-spraying polyvinylpyrrolidone (PVP, a model pharmaceutical binder) with various l-leucine concentrations were used for this study. Paracetamol was used as model active pharmaceutical ingredient (API). The surface energy was used to derive the work of cohesion (wco) and work of adhesion (wad) to predict the interactive mixing behaviour of the excipients with paracetamol. The blends were visualised under a scanning electron microscopy microscope to assess the interactive mixing behaviour. In addition, the flow performance and tabletting behaviour of various blends were characterised. RESULTS: The surface-energy derived work of adhesion (wad) between excipient and paracetamol particles increased, while the corresponding work of cohesion (wco) between excipient particles decreased, with increasing l-leucine concentrations. In blends for which the work of cohesion was higher than the work of adhesion (wco>wad), small excipient particles were apparent as agglomerates. For excipients with 5% and higher l-leucine concentrations, the work of adhesion between excipient and paracetamol particles was higher than or equivalent to the work of cohesion between excipient particles (wad⩾wco) and agglomerates were less apparent. This is an indicator of formation of homogeneous interactive mixtures. At 5% (w/w) excipient proportions, blends for which wad⩾wco demonstrated higher compactibility than other blends. Furthermore, at 10% (w/w) and higher excipient proportions, these blends also demonstrated better flow performance than other blends. CONCLUSION: In conclusion, this is the first study to demonstrate that surface-energy derived CAB data effectively predict the interactive mixing behaviour of small excipient particles. Furthermore, at certain proportions of small excipient particles the CAB model also predicts the flow and compaction behaviour of the API/excipient blends.

On the Methods to Measure Powder Flow.

The flow of powders can often play a critical role in the manufacturing of pharmaceutical products. Many of these processes require good, consistent and predictable flow of powders to ensure continuous production of pharmaceutical dosages and to ensure their quality. Therefore, the flow of powders is of paramount importance to the pharmaceutical industry and thus the measuring and evaluating of powder flow is of utmost importance. At present, there are numerous methods in which the flow of powders can be measured. However, due to the complex and environment-dependent nature of powders, no one method exists that is capable of providing a complete picture of the behaviour of powders under dynamic conditions. Some of the most commonly applied methods to measure the flow of powders include: density indices, such as the Carr index and Hausner ratio, powder avalanching, the angle of repose (AOR), flow through an orifice, powder rheometry and shear cell testing.

Relationship between surface concentration of L-leucine and bulk powder properties in spray dried formulations.

The amino acid L-leucine has been demonstrated to act as a lubricant and improve the dispersibility of otherwise cohesive fine particles. It was hypothesized that optimum surface L-leucine concentration is necessary to achieve optimal surface and bulk powder properties. Polyvinylpyrrolidone was spray dried with different concentration of L-leucine and the change in surface composition of the formulations was determined using X-ray photoelectron spectroscopy (XPS) and time of flight-secondary ion mass spectrometry (ToF-SIMS). The formulations were also subjected to powder X-ray diffraction analysis in order to understand the relationship between surface concentration and solid-state properties of L-leucine. In addition, the morphology, surface energy and bulk cohesion of spray dried formulations were also assessed to understand the relation between surface L-leucine concentration and surface and bulk properties. The surface concentration of L-leucine increased with higher feed concentrations and plateaued at about 10% L-leucine. Higher surface L-leucine concentration also resulted in the formation of larger L-leucine crystals and not much change in crystal size was noted above 10% L-leucine. A change in surface morphology of particles from spherical to increasingly corrugated was also observed with increasing surface l-leucine concentration. Specific collapsed/folded over particles were only seen in formulations with 10% or higher l-leucine feed concentration suggesting a change in particle surface formation process. In addition, bulk cohesion also reduced and approached a minimum with 10% L-leucine concentration. Thus, the surface concentration of L-leucine governs particle formation and optimum surface L-leucine concentration results in optimum surface and bulk powder properties.

Reprint of: DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment.

Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus.

DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment.

Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus.

Utilizing temporal information in fMRI decoding: classifier using kernel regression methods.

This paper describes a general kernel regression approach to predict experimental conditions from activity patterns acquired with functional magnetic resonance image (fMRI). The standard approach is to use classifiers that predict conditions from activity patterns. Our approach involves training different regression machines for each experimental condition, so that a predicted temporal profile is computed for each condition. A decision function is then used to classify the responses from the testing volumes into the corresponding category, by comparing the predicted temporal profile elicited by each event, against a canonical hemodynamic response function. This approach utilizes the temporal information in the fMRI signal and maintains more training samples in order to improve the classification accuracy over an existing strategy. This paper also introduces efficient techniques of temporal compaction, which operate directly on kernel matrices for kernel classification algorithms such as the support vector machine (SVM). Temporal compacting can convert the kernel computed from each fMRI volume directly into the kernel computed from beta-maps, average of volumes or spatial-temporal kernel. The proposed method was applied to three different datasets. The first one is a block-design experiment with three conditions of image stimuli. The method outperformed the SVM classifiers of three different types of temporal compaction in single-subject leave-one-block-out cross-validation. Our method achieved 100% classification accuracy for six of the subjects and an average of 94% accuracy across all 16 subjects, exceeding the best SVM classification result, which was 83% accuracy (p=0.008). The second dataset is also a block-design experiment with two conditions of visual attention (left or right). Our method yielded 96% accuracy and SVM yielded 92% (p=0.005). The third dataset is from a fast event-related experiment with two categories of visual objects. Our method achieved 77% accuracy, compared with 72% using SVM (p=0.0006).

Developmental influences on the neural bases of responses to social rejection: implications of social neuroscience for education.

Relational aggression such as social rejection is common within school peer groups. Converging evidence suggests that adolescent females are particularly sensitive to social rejection. We used a novel fMRI adaptation of the Cyberball social rejection paradigm to investigate the neural response to social rejection in 19 mid-adolescent (aged 14-16) and 16 adult female participants. Across all participants, social exclusion (relative to inclusion) elicited a response in bilateral medial prefrontal cortex (mPFC) extending into ventral and subgenual anterior cingulate cortex and medial orbitofrontal cortex; and the left ventrolateral PFC (vlPFC); regions that have been associated in previous studies with social evaluation, negative affective processing, and affect regulation respectively. However, the exclusion-related response in right vlPFC, a region associated in previous studies with the regulation of rejection-related distress, was attenuated in adolescents. Within mPFC, greater activation during exclusion vs. inclusion was associated with greater self-reported susceptibility to peer influence in adolescents but not in adults. This suggests that the brain's response to experimentally-induced social rejection relates to adolescent behaviour in real-world social interactions. We speculate about the potential implications of these findings for educational settings. In particular, functional development of affective circuitry during adolescence may influence social interaction within the school peer group.

Kernel regression for fMRI pattern prediction.

This paper introduces two kernel-based regression schemes to decode or predict brain states from functional brain scans as part of the Pittsburgh Brain Activity Interpretation Competition (PBAIC) 2007, in which our team was awarded first place. Our procedure involved image realignment, spatial smoothing, detrending of low-frequency drifts, and application of multivariate linear and non-linear kernel regression methods: namely kernel ridge regression (KRR) and relevance vector regression (RVR). RVR is based on a Bayesian framework, which automatically determines a sparse solution through maximization of marginal likelihood. KRR is the dual-form formulation of ridge regression, which solves regression problems with high dimensional data in a computationally efficient way. Feature selection based on prior knowledge about human brain function was also used. Post-processing by constrained deconvolution and re-convolution was used to furnish the prediction. This paper also contains a detailed description of how prior knowledge was used to fine tune predictions of specific "feature ratings," which we believe is one of the key factors in our prediction accuracy. The impact of pre-processing was also evaluated, demonstrating that different pre-processing may lead to significantly different accuracies. Although the original work was aimed at the PBAIC, many techniques described in this paper can be generally applied to any fMRI decoding works to increase the prediction accuracy.

Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2.

Recent genetic studies have implicated a number of candidate genes in the pathogenesis of Autism Spectrum Disorder (ASD). Polymorphisms of CNTNAP2 (contactin-associated like protein-2), a member of the neurexin family, have already been implicated as a susceptibility gene for autism by at least 3 separate studies. We investigated variation in white and grey matter morphology using structural MRI and diffusion tensor imaging. We compared volumetric differences in white and grey matter and fractional anisotropy values in control subjects characterised by genotype at rs7794745, a single nucleotide polymorphism in CNTNAP2. Homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation. Thus a risk allele for autism results in significant cerebral morphological variation, despite the absence of overt symptoms or behavioural abnormalities. The results are consistent with accumulating evidence of CNTNAP2's function in neuronal development. The finding suggests the possibility that the heterogeneous manifestations of ASD can be aetiologically characterised into distinct subtypes through genetic-morphological analysis.

Voxel-based morphometry reveals reduced grey matter volume in the temporal cortex of developmental prosopagnosics.

Individuals with developmental prosopagnosia exhibit severe and lasting difficulties in recognizing faces despite the absence of apparent brain abnormalities. We used voxel-based morphometry to investigate whether developmental prosopagnosics show subtle neuroanatomical differences from controls. An analysis based on segmentation of T1-weighted images from 17 developmental prosopagnosics and 18 matched controls revealed that they had reduced grey matter volume in the right anterior inferior temporal lobe and in the superior temporal sulcus/middle temporal gyrus bilaterally. In addition, a voxel-based morphometry analysis based on the segmentation of magnetization transfer parameter maps showed that developmental prosopagnosics also had reduced grey matter volume in the right middle fusiform gyrus and the inferior temporal gyrus. Multiple regression analyses relating three distinct behavioural component scores, derived from a principal component analysis, to grey matter volume revealed an association between a component related to facial identity and grey matter volume in the left superior temporal sulcus/middle temporal gyrus plus the right middle fusiform gyrus/inferior temporal gyrus. Grey matter volume in the lateral occipital cortex was associated with component scores related to object recognition tasks. Our results demonstrate that developmental prosopagnosics have reduced grey matter volume in several regions known to respond selectively to faces and provide new evidence that integrity of these areas relates to face recognition ability.

From threat to fear: the neural organization of defensive fear systems in humans.

Postencounter and circa-strike defensive contexts represent two adaptive responses to potential and imminent danger. In the context of a predator, the postencounter reflects the initial detection of the potential threat, whereas the circa-strike is associated with direct predatory attack. We used functional magnetic resonance imaging to investigate the neural organization of anticipation and avoidance of artificial predators with high or low probability of capturing the subject across analogous postencounter and circa-strike contexts of threat. Consistent with defense systems models, postencounter threat elicited activity in forebrain areas, including subgenual anterior cingulate cortex (sgACC), hippocampus, and amygdala. Conversely, active avoidance during circa-strike threat increased activity in mid-dorsal ACC and midbrain areas. During the circa-strike condition, subjects showed increased coupling between the midbrain and mid-dorsal ACC and decreased coupling with the sgACC, amygdala, and hippocampus. Greater activity was observed in the right pregenual ACC for high compared with low probability of capture during circa-strike threat. This region showed decreased coupling with the amygdala, insula, and ventromedial prefrontal cortex. Finally, we found that locomotor errors correlated with subjective reports of panic for the high compared with low probability of capture during the circa-strike threat, and these panic-related locomotor errors were correlated with midbrain activity. These findings support models suggesting that higher forebrain areas are involved in early-threat responses, including the assignment and control of fear, whereas imminent danger results in fast, likely "hard-wired," defensive reactions mediated by the midbrain.