Future work

2. Research Plan

2.1. Neural correlates of social brain and functional connectivity

As mentioned in the previous section, the neural system, including the amygdala and related structures, i.e., the social brain regulates social and emotional behavior in humans. Research aimed at investigating the function of the social brain network will contribute to elucidating the neurobiological mechanisms underlying neuropsychiatric disorders such as depression, panic disorder, schizophrenia, and PTSD. The proposed study aims at clarifying how neuronal interactions between the amygdala and other parts of the network are orchestrated in human subjects exposed to various social circumstances.

Specifically, the aversive conditioning paradigm and fMRI experiments may help in understanding the neuronal activity that governs the responses of normal subjects to psychosocial stress and the perception of negative emotions expressed by other persons. By altering the relationship between the conditioned and unconditioned stimuli used in the experiment, we may be able to study the neural processing associated with the inhibition and extinction of unwanted emotional memories. In addition, we can simulate the neural mechanisms that determine the effectiveness of exposure therapy for the PTSD patients. We also intend to study sex differences in the brain activity associated with aversive learning and stress responses.

Another approach for clarifying the mechanisms of neuronal interactions is to examine the neuronal connectivity between the brain regions by using diffusion tensor imaging (DTI). DTI is an MRI technique that has recently been used to investigate the microstructural properties of white matter in the brain (Takahashi et al.,2010). If fMRI and DTI images are obtained for a single subject by using the same scanner, the fiber connections between the functional regions of the brain can be visualized. The strength of the fiber connections between the activated clusters is expected to correlate with the subject’s personality traits, ability to perform tasks, and degree of social adjustment.

If fMRI and DTI analysis reveal the precise location of social behavior components, it may be possible to intervene this system with transcranial magnetic stimulation (TMS). TMS enhances or inhibits neuronal activity in areas of the brain surface and alters the performance of tasks related to several domains of cognition and emotion. In addition, monitoring the hemodynamic responses by using a combination of near-infrared spectroscopy (NIRS) and TMS would help us identify the region-specific effects of magnetic stimulation on brain activity.

2.2. Effect of brain-gene interaction on social brain (imaging genetics)

Imaging genetics is a powerful and non-invasive approach that can be used to investigate the interactions among the brain, mind, and genes. The procedure is as follows: Blood or saliva samples are collected from the subjects who have undergone fMRI and performed a task requiring the social brain. The sample is genotyped to detect an SNP associated with neuronal development and the functioning of the neurotransmitter system. The subjects are divided into 2 or 3 subgroups according to the genotypes determined, and the brain activity is compared among the subgroups. Assuming that the results of fMRI, genotyping, and psychological task assessment will support our specific hypothesis, this study will improve the understanding of the link between brain, mind, and gene.

The brain-derived neurotrophic factor (BDNF) is a key protein responsible for neuronal development and plasticity and its function is related to learning, memory, and stress responses. An SNP (rs6265) in the BDNF gene, involving the substitution of guanine and adenine to result in a valine and methionine variation in codon 66 (val66met), has frequently been studied. Experiments on animals and association studies on patients with depression have revealed the relationship between this SNP and susceptibility to stress. We aim to elucidate the significance of this BDNF polymorphism in aversive conditioning; we predict that the amygdala and/or hippocampal activity is modulated by this SNP. In addition, we plan to investigate other candidate genes associated with cognitive function and the neurotransmitter system, such as 5-HTTLPR, catechol-O-methyltransferase (COMT), monoamine oxidase-A (MAO-A), and dopamine receptor DR3 (DRD3).

2.3. Cultural neuroscience and emotions

Cultural psychologists have long argued that culture significantly influences personality, social behavior, and self-construal. Several studies have examined the influence of culture on the perception of facial expressions, and they have revealed that negative facial expressions are perceived differently by different cultural groups. Furthermore, cultural values such as individualism and collectivism affect the emotional intensity perceived in the faces of other individuals. “Cultural neuroscience” has recently emerged as a subcategory in the field of neuroscience (Chiao et al., 2010). Cultural neuroscience studies aim at elucidating the differences and similarities between the cultural groups in terms of brain function and addressing the long-standing issue of “nature versus nurture.”

We plan to extend this approach to several cultural groups: native Japanese in Japan, American Japanese in the US, and Caucasians in the US. In order to measure the activity in the amygdala, we will perform fMRI on these subjects, while they perform an emotion-processing task. Furthermore, we will genotype samples obtained from the subjects in order to detect several candidate SNPs. Intergroup comparisons will be performed considering the main effects of cultural group and genotype and their interaction effect. We predict that the main effect of cultural group will significantly modulate the amygdala activity during the emotion processing task, and that a particular group may thus be more vulnerable to stress. These experiments will be conducted in collaboration with Dr. Joan Chiao at Northwestern University, Department of Psychology. We have been collaborating since 2006 with the financial support from Japan Society for the Promotion of Sciences and National Science Foundation in the US.

2.4. Resting state functional connectivity as a disease biomarker

Psychiatric disorders are still diagnosed using symptomatic criteria and, to date, clinically useful biological markers based on the neurological and genetic origins of these diseases have not been developed. However, there are numerous findings indicating altered brain activity in patients with psychiatric disorders such as schizophrenia and autism compared to healthy controls. These results were obtained during performance of a cognitive task, and during resting state (rs), and were measured using fMRI. Therefore, neural activity, as measured by fMRI, could be a biomarker of disease onset, response to medication, and prognosis. In particular, rs-fMRI is easily assessed in a clinical setting because there is no need for task instruction or participant response. In our previous study (Iidaka, 2015), we accurately classified a large set of rs-fMRI data from participants with autism or neurotypical development using connectivity analysis and machine learning algorithms..

2.5. Long-term goal of the proposed study

The proposed study will expand the current knowledge of neuroscience from social, cultural, and affective perspectives. Specifically, understanding the complex behavior of humans and identifying the underlying brain mechanisms could contribute to the development of non-invasive and non-pharmacological approaches for ameliorating maladaptation to and withdrawal from social circumstances. My findings regarding the functions of the social brain in adult humans could be extended to future studies on younger subjects and infants for elucidating the neuronal mechanism underlying the development of “empathy,” which is a crucial mental ability to understand another person’s emotions and feelings. Finally, long-term goal of the project is to elucidate the neural correlates of “humanity” that involves empathy, fairness, and morality.