Geoffrey Tan

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.

A Genetically Mediated Bias in Decision Making Driven by Failure of Amygdala Control

Genetic variation at the serotonin transporter-linked polymorphic region (5-HTTLPR) is associated with altered amygdala reactivity and lack of prefrontal regulatory control. Similar regions mediate decision-making biases driven by contextual cues and ambiguity, for example the “framing effect.” We hypothesized that individuals hemozygous for the short (s) allele at the 5-HTTLPR would be more susceptible to framing. Participants, selected as homozygous for either the long (la) or s allele, performed a decision-making task where they made choices between receiving an amount of money for certain and taking a gamble. A strong bias was evident toward choosing the certain option when the option was phrased in terms of gains and toward gambling when the decision was phrased in terms of losses (the frame effect). Critically, this bias was significantly greater in the ss group compared with the lala group. In simultaneously acquired functional magnetic resonance imaging data, the ss group showed greater amygdala during choices made in accord, compared with those made counter to the frame, an effect not seen in the lala group. These differences were also mirrored by differences in anterior cingulate–amygdala coupling between the genotype groups during decision making. Specifically, lala participants showed increased coupling during choices made counter to, relative to those made in accord with, the frame, with no such effect evident in ss participants. These data suggest that genetically mediated differences in prefrontal–amygdala interactions underpin interindividual differences in economic decision making.

Interpreting scan data acquired from multiple scanners: A study with Alzheimer's disease

Large, multi-site studies utilizing MRI-derived measures from multiple scanners present an opportunity to advance research by pooling data. On the other hand, it remains unclear whether or not the potential confound introduced by different scanners and upgrades will devalue the integrity of any results. Although there are studies of scanner differences for the purpose of calibration and quality control, the current literature is devoid of studies that describe the analysis of multi-scanner data with regard to the interaction of scanner(s) with effects of interest. We investigated a data-set of 136 subjects, 62 patients with mild to moderate Alzheimers disease and 74 cognitively normal elderly controls, with MRI scans from one center that were acquired over 10 years with 6 different scanners and multiple upgrades over time. We used a whole-brain voxel-wise analysis to evaluate the effect of scanner, effect of disease, and the interaction of scanner and disease for the 6 different scanners. The effect of disease in patients showed the expected significant reduction of grey matter in the medial temporal lobe. Scanner differences were substantially less than the group differences and only significant in the thalamus. There was no significant interaction of scanner with disease group. We describe the rationale for concluding that our results were not confounded by scanner differences. Similar analyses in other multi-scanner data-sets could be used to justify the pooling of data when needed, such as in studies of rare disorders or in multi-center designs.

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.

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 brains 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.

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 CNTNAP2s 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.

Automatic detection of preclinical neurodegeneration Presymptomatic Huntington disease

Background: Treatment of neurodegenerative diseases is likely to be most beneficial in the very early, possibly preclinical stages of degeneration. We explored the usefulness of fully automatic structural MRI classification methods for detecting subtle degenerative change. The availability of a definitive genetic test for Huntington disease (HD) provides an excellent metric for judging the performance of such methods in gene mutation carriers who are free of symptoms. Methods: Using the gray matter segment of MRI scans, this study explored the usefulness of a multivariate support vector machine to automatically identify presymptomatic HD gene mutation carriers (PSCs) in the absence of any a priori information. A multicenter data set of 96 PSCs and 95 age- and sex-matched controls was studied. The PSC group was subclassified into three groups based on time from predicted clinical onset, an estimate that is a function of DNA mutation size and age. Results: Subjects with at least a 33% chance of developing unequivocal signs of HD in 5 years were correctly assigned to the PSC group 69% of the time. Accuracy improved to 83% when regions affected by the disease were selected a priori for analysis. Performance was at chance when the probability of developing symptoms in 5 years was less than 10%. Conclusions: Presymptomatic Huntington disease gene mutation carriers close to estimated diagnostic onset were successfully separated from controls on the basis of single anatomic scans, without additional a priori information. Prior information is required to allow separation when degenerative changes are either subtle or variable.

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.

Effects of age and MAOA genotype on the neural processing of social rejection

Adolescents are often sensitive to peer rejection, a factor that might contribute to the risk of affective disorder in this age group. Previous studies suggest a significant overlap among socioaffective brain regions involved in the response to social rejection, regions continuing to develop functionally during adolescence and regions influenced by monoamine oxidase A (MAOA) polymorphism. The current study investigated whether the neural response to social rejection is functionally immature in adolescents compared with adults, and whether these responses are modulated by MAOA genotype. Blood‐oxygen‐level‐dependent response was measured with functional magnetic resonance imaging during a rejection‐themed emotional Stroop task in 19 adolescents (aged 14–16) and 16 adults (aged 23–28) genotyped for MAOA polymorphism. Similar numbers of MAOA‐L and MAOA‐H carriers were recruited to maximize power to detect genotype effects. Main effects of rejection stimuli (relative to neutral and acceptance control stimuli) were seen in predicted socioaffective brain regions. Adolescents did not show the adult pattern of modulation by rejection stimuli in the right ventrolateral prefrontal cortex, suggesting continued functional maturation of this regulatory region during adolescence. Age and genotype interacted in the left amygdala, in which the predicted effect of genotype on responses to rejection stimuli was seen in the adults, but not in the adolescents. The data suggest continued functional development of the circuitry underlying the processing of social rejection between adolescence and adulthood, and show that the effects of MAOA genotype on neural responses may vary with age.

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.