The affective bases of psychiatric disorders continue to be a central question in clinical neuroscience research. Disorders such as schizophrenia, and of mood and anxiety have been associated with impaired affective appraisal and regulation, and resultant impairments in social function and interaction . With regards to schizophrenia specifically, retrospective studies of large scale cohorts have documented widespread impairments in social interaction and function during (pre-morbid) adolescence . These results indicate the emergence of social impairments during critical stages of development in the illness. Social interactions in part rely on intact cortico-limbic function, suggesting that functional alterations particularly in limbic circuitry may impair the appraisal of social cues, and by consequence social behavior.
Impairments in social interaction have also been documented in healthy adolescent offspring of schizophrenia patients. Moreover, estimated incidence rates of schizophrenia-related psychosis or otherwise unspecified psychosis range in offspring of schizophrenia patients (SCZ-Off) range from eight to 20 percent . Though the rates of conversion to the narrowly defined clinical phenotype of schizophrenia may be relatively low, the incidence of Axis I psychopathology is relatively high in this population . In addition, studies of brain function and structure suggest that compared to controls with no family history of psychiatric illness, schizophrenia offspring show widespread deficits . Whereas longitudinal studies that quantify rates of conversion to schizophrenia are lacking, these cross-sectional data indicate that SCZ-Off are vulnerable to developmentally mediated deficits of structural and functional biology which in turn may predispose them to become manifestly ill later in life.
Prospective studies examining the offspring of schizophrenia patients find increased incidence of anhedonia, social withdrawal, affective flattening, poor global adjustment, and poor social competence . Additionally, this population shows a high occurrence (20–50 percent) of schizotaxia disorder, characterized by negative symptoms and neuropsychological dysfunction . Altered limbic system activity may play a crucial role in the neurobiology of the hypothesized affective and social deficits in this population. In particular, impaired responses in key limbic structures during affective appraisal may negatively impact the response to affective facial cues. Finally, given the exquisite developmental expansion that is needed to subserve the normal development of emotional appraisal and processing , offspring who are characterized by developmental derailment may also show altered developmental patterns in their appraisal of stimuli.
The observed affect deficits in SCZ-Off are generally consistent with studies in schizophrenia itself. The altered appraisal of social stimuli is a recognized impairment among schizophrenia patients, and while a complete understanding of the neural bases of these abnormalities is still emerging, studies on emotional face processing in patients suggest state-independent, diminished amygdala activation compared to controls . However, the amygdala is not a functionally homogenous structure. Studies have identified functionally distinguishable sub-regions with separable efferents and afferents to other regions of the brain . Understanding how the intra-amygdala circuit responds in risk, vulnerability and disease may greatly enhance the understanding of how the affective response contributes to behavior and psychiatric illness.
1.1. The emotional centers of the brain: The intra-amygdala circuit
The amygdala is an essential emotional center of the brain which drives emotional processing and output, and amygdala dysfunction underlies emotional and conduct disorders . Functional neuroimaging and PET studies show that both positive and negative emotions drive amygdala activity , yet how the amygdala influences behavioral responses to affect is yet not entirely resolved. Work in the basic neuroscience of emotion has revealed reciprocal influences between the amygdala and other cortical and sub-cortical centers, and these influences may offer rich models linking amygdala function, social behavior and psychiatric disorders. Thus, just as cortical areas influence processing within amygdala nuclei , projections from the amygdala to cortical areas as well as autonomic and reward centers in the cortex and brainstem may in turn influence behavioral responses to emotional stimuli or situations.
Specific patterns of sensory information transmission within amygdala subregions suggest a relative segregation of intra-amygdala function. After information from the sensory cortices enters the amygdala through the lateral nucleus (located in the baso-lateral area [BA]) , adaptive filtering occurs. The lateral nucleus transmits information to the basal and central nuclei , which further process information via intra- and inter-divisional nuclear projections . The basolateral nucleus has been most recently associated with the experience of anxiety , and extensively projects to ventral regions of the frontal cortex, as well as reward related regions such as the nucleus accumbens . Further, the central (or centro-medial) nucleus receives information from all other nuclei, and serves as a key site for signal projections to the cortex, the brainstem and hypothalamic autonomic centers, and may be a critical site for signal integration and output affecting behavior . provides a conceptual model of perceptual information flow from sensory cortices to the amygdala, affective information flow within key amygdala nuclei, and the translation of affective evaluation/response in the amygdala to regions involved in autonomous behavioral regulation and response. As the model implies, the response of key sub-regions within the amygdala such as the basolateral and centro-medial nuclei to affectively valenced stimuli may be crucial in mediating behavioral responses. Combining fMRI data with probabilistic maps of the intra-amygdala nuclei may allow the estimation of, and separation of activity within the intra-amygdala circuit.
Figure 1 The figure depicts a conceptual model of affective information flow from sensory to cortical regions via intra-amygdala interactions. As noted in the text, adaptive filtering within the amygdala pathways results in relative specialization and specific (more ...)
1.2 Cyto-architectonic maps to assess the intra-amygdala circuit
Recent advances in quantitative cytoarchitectonic mapping facilitate the identification of intra-amygdala activity in vivo by associating brain activation to their cytoarchitectonic origins using a probabilistic atlas . The details have been extensively documented elsewhere . In brief these techniques rely on observer-independent characterization of architectonics in human post-mortem brains followed by an MRI-based probabilistic quantitation of how these cytoarchitectonic regions are mapped into stereotactic space . The ensuing cytoarchitectonic probability maps quantify both location and spatial variability of the respective areas by identifying spatial regions of high convergence against regions of low convergence across sampled post-mortem brains. (left) shows bilateral probabilistic distributions of the baso-lateral and centro-medial nuclei in stereotactic space . The map depicts the considerable spatial variability across samples (see adjacent probability scale). Corresponding maximum probability maps (right, shown for the left hemisphere) are derived by assigning each voxel of the reference space to the most likely anatomical area at the respective position, yielding a continuous, non-overlapping summary based on individual probabilistic maps . This emerging field of combining cytoarchitectonic maps with fMRI has resulted in advances in the mapping of the somatosensory system and activity in Broca’s area (Brodmann areas 44 & 45) and the amygdala , yet the current application is, to our knowledge, the first to estimate intra-amygdala activity differences in developmentally vulnerable populations.
Figure 2 The relationship between quantified spatial probability maps (left) of the centro-medial (top) and baso-lateral (bottom) and corresponding maximum probability maps is depicted in single axial and coronal sections. Note that the maximum probability maps (more ...)
Altered limbic system activity may play a crucial role in the neurobiology of the hypothesized affective and social deficits in young offspring of schizophrenia patients . In particular, impaired responses in key limbic structures may result in abnormal signaling to regions modulating behavior, thereby negatively impacting social interaction. It is plausible that limbic impairments precede the manifestation of behavioral impairments and therefore are a leading indicator of behavioral problems that may follow . We used fMRI to investigate the amygdala response, and the response of individual amygdala nuclei to the appraisal of affectively valenced faces in a group of adolescent SCZ-Off and controls (HC) with no family history of psychiatric illness (to the 2nd degree). Given longitudinal and cross-sectional evidence of progressive deficits in function in SCZ-Off , we also assessed age-related changes in the amygdala response through adolescence in each of the groups.