Research aim

Imaging of social brain network: from affective, cultural, and genetic perspectives: Application to neuroscience and psychiatry

1. Background

1.1. General background

Recently, there has been growing concern worldwide with regard to psychosocial stress and suicidal behavior. The number of suicidal deaths in Japan has increased since 1998 and has now exceeded 30,000 deaths per year. The rate in Japan is the highest among the developed countries both among males and females. In addition, the prevalence rate of psychiatric diseases such as depression, panic disorder, and post-traumatic stress disorder (PTSD) is dramatically increasing in westernized countries. In light of these facts, the investigation of neural mechanisms involving stress responses and emotion has gained maximum priority in neuroscience research.

Another matter of concern is the anti-social behavior and social withdrawal often observed among the younger generation. These characteristics are considered to stem from a lack of interpersonal communication skills and environmental factors such as the decreasing number of children. The expression of one’s own emotion and the evaluation of others’ emotions are important communicative skills in primates, including humans. Infants communicate with their parents by looking at their faces and listening to their voices. A prototype of face-recognition system is present in the brain at birth, and its normal development is crucial for social communication.

In the field of neuroscience research, the assessment of stress responses, emotions, and social communication in primates, including humans, is emerging as an important area. Previous studies on primates or humans with brain injury have revealed that the amygdala plays a critical role in emotions, fear responses, and face recognition. The neural network, which involves the amygdala and related structures such as the prefrontal cortex (PFC), fusiform gyrus, and superior temporal gyrus, is thought to exhibit critical activity when human subjects are engaged in social behavior; this network is therefore referred to as the “social brain.”

Neuroimaging methods such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) enable non-invasive investigation of the social brain function with high spatial resolution. The next section of this research proposal describes my experience with neuroimaging methods such as 3-Tesla MRI and event-related potential (ERP) performed on normal human subjects and patients with neuropsychiatric disorders.

1.2. Previous studies conducted at our laboratory

1.2.1. Neural activation of the social brain in humans during explicit and implicit face processing.

Although the involvement of the human amygdala in the processing of facial expressions has been investigated, the neural mechanisms underlying motivated or emotional behavior in response to facial stimuli are not fully understood. We used 3-Tesla fMRI to investigate the interaction between the amygdala and other cortical regions in healthy volunteers. The experiment was conducted while the subjects were looking at images of facial expressions. The results revealed that the left amygdala was predominantly involved in the processing of negative expressions. The activity in the left amygdala positively correlated with that in the left PFC during the processing of negative facial expressions. This finding suggests that the left amygdala, together with the PFC, plays a role in the effective processing of observed negative emotions. (Iidaka et al., 2001)

The association between the amygdala and the PFC during the evaluation of facial expressions was examined by fMRI while the subjects performed a subliminal affective priming task. The subjects were shown a prime image of an angry or neutral face (for 35 ms), followed by the target faces. The subjects could not consciously identify the prime images presented. We found that the activity in the right amygdala was greater with subliminal presentation of the angry face than with that of the neutral face. Further, activity in the amygdala correlated with that in the right PFC and with the subject’s judgment of the target faces. These results indicated the functional association between the right PFC and the amygdala and its influence on cognitive processing. (Nomura et al., 2004)

Thus, neuroimaging studies have revealed that the PFC, together with the amygdala, plays a critical role in the cognitive evaluation of facial expressions. To further this concept, we investigated the PFC-amygdala interaction during voluntary emotion regulation by presenting affective pictures to healthy subjects and instructing the subjects to express or suppress their emotion. We measured the cerebral blood flow while simultaneously measuring the autonomic and hormonal responses. We found that the left amygdala was activated during the attending task, whereas the PFC was activated during the suppression task. In the attending task, the activity in the amygdala positively correlated with the magnitudes of the autonomic and hormonal responses. These results suggest that PFC-controlled suppression of emotions influenced the amygdala activity and peripheral responses. (Ohira et al., 2006)

1.2.2. Comparison of the amygdala responses between normal subjects and other subject groups (schizophrenic patients, normally aging subjects, and individuals of other ethnicities).

Although facial expression recognition is reported to be impaired in schizophrenic patients, the neural mechanism underlying this impairment is not fully understood. To investigate this mechanism, we performed fMRI on schizophrenic patients and healthy controls. When the subjects were presented images of positive facial expressions, the activity in the right amygdala was significantly greater in the schizophrenic group than in the control group. The exaggerated activity in the amygdala observed in the patients may reflect impaired gating of the sensory input, which controls emotion. (Kosaka et al., 2002)

Next, we investigated the age-related differences in the neural substrates involved in facial emotion perception in young and old healthy subjects. The results revealed a significant age-related difference in the left amygdala activity during the perception of negative facial expressions: the activity was enhanced in young subjects and reduced in old subjects. These results indicate that the age-associated decline in the amygdala activity may represent a neural basis for the difficulty in recognizing facial emotions in elderly people. (Iidaka et al., 2002)

Culture shapes several aspects of emotional and social behavior, including the perception of fear and its expression to others; however, little is known about how culture influences neural responses to fear stimuli. We used fMRI to evaluate and compare the amygdala responses to images of faces expressing fear in native Japanese in Japan and Caucasians in the US. The results revealed that among the subjects of both groups, the amygdala activity was greater in response to fear expressed by members of the same cultural group. This finding provides novel evidence of how culture influences the automatic neural responses. (Chiao et al., 2008)

1.2.3. Imaging genetics approach for understanding emotional responses of the human amygdala and PFC.

Imaging genetics is an experimental approach in which brain-gene interactions are investigated using a combination of fMRI and genetic analysis. The serotonin (5-HT) system within the brain has been linked to various components of human behavior, such as mood and anxiety. To investigate the link between the 5-HT system and the amygdala activity, we genotyped normal subjects who underwent fMRI and face recognition tasks in terms of the single nucleotide polymorphism (SNP) C178T in the regulatory region of the serotonin receptor type 3 gene (HTR3A). We found that the subjects carrying C/C alleles showed greater amygdala activity than those with C/T alleles. These results indicate that the C178T variation in HTR3A critically influences the amygdala activity and facial expression processing, probably by regulating the expression of the serotonin type 3 receptor. (Iidaka et al., 2005)

The relationship between the serotonin transporter linked polymorphic region (5-HTTLPR) and stress responses has been investigated in studies involving fMRI and genetic analysis. These studies have demonstrated that homozygous carriers of the 5-HTTLPR s allele, who are vulnerable to stress, exhibit greater amygdala activation than homozygous carriers of the l allele (Hariri et al., 2002). We investigated whether the response to a face stimulus could be conditioned by using a voice with a negative emotional valence, and whether the activity of the social brain components would differ among subjects with different 5-HTTLPR genotypes. We noted consistent PFC activation in response to faces paired with the voice than in response to faces alone. On the other hand, the right amygdala showed transient activation during the acquisition phase (Iidaka et al., 2010). The results of imaging genetics revealed that the effect of 5-HTTLPR on brain activity were reflected in the PFC rather than in the amygdala. The reduced dorsolateral PFC activity noted in subjects carrying 2 s alleles may be related to the susceptibility of these subjects to psychosocial stress. (Iidaka et al., in preparation)