The anterior cingulate cortex (ACC) plays an important role in reward-based decision-making, linking higher-order thinking and emotions. Because of this area's dense connectivity it is important to study the properties of the excitatory and inhibitory network that governs ACC output. The aim of this study was to characterize the morphology of dendritic excitatory postsynaptic sites and inhibitory inputs on layer 2 and layer 3 ACC pyramidal neurons, the principal intracortical projection neurons of the cortex. Using biocytin-filling and high-resolution confocal imaging, we quantified the distribution of dendritic spines, the major sites of excitatory input, on pyramidal cells. We visualized inhibitory inputs apposed to specific pyramidal cell compartments, including the axon initial segment, soma, dendrites, and dendritic spines, through immunohistochemical labeling of vesicular γ-aminobutyric acid transporter. Layer 2 and layer 3 cells had similar spine densities on their apical and basal dendritic compartments, with a maximum spine density occurring in their middle apical and middle basal compartments. Axon initial segments of layer 3 cells had a higher density of inhibitory input compared to the layer 2 cells (0.84 vs 0.66 apps/μm). The apical dendritic shaft had a higher apposition density than the basal dendritic shaft in an individual layer (layer 2, 0.50 vs 0.32; layer 3, 0.50 vs 0.28 apps/μm) with the majority of the innervation occurring on the proximal compartments of both apical and basal segments. Although located in different laminae, these cells showed similar inhibitory input distributions, with higher amounts of inhibition proximally. Finally, these inhibitory inputs also occurred on dendritic spines, with the highest density on thin spines. However, proportionally, mushroom spines had the highest level of innervation, with up to 44% of these spines receiving inhibitory input. These findings add to the understanding of how inhibition at the cellular level can affect the output of the ACC and begin to uncover important relationships between cellular structure and function in this brain region.

In recent years Social Neuroscience has started to investigate how mood and culture influence social and emotional situations. In the present study differences in elicited emotion and neural activation were investigated when participants viewed films depicting social interactions. Film clips are preferred stimuli for elicitation of emotion in laboratory studies, but given the lack of standardised film sets in the literature, two behavioural studies were conducted prior to imaging. The first study (147 females, 30 males; 98.8% 18 to 24 years) identified a set of clips that elicited emotion profiles in which the target emotion (happy, sad) was strongest, as well as neutral clips, and demonstrated an effect of participants’ stable mood. The second study (143 females, 19 males; mean age 19.2 years) optimised the stimulus set and demonstrated effects of self-reported ethnic origin, mood and interest on profiles of elicited emotion. In the fMRI investigation 33 female and 8 male participants (mean age 19.2 years) viewed film clips in a block design experiment with loose and tight t-contrasts and retrospective ratings of elicited emotion. Across all-participants, social interaction depicting sadness activated key emotion-related structures such as left amygdala and insula, and medial frontal cortex that were not significantly activated with social interaction depicting happiness. However, greater activation was observed for Europeans than for non-Europeans in orbitofrontal cortex, anterior and posterior cingulate for happy social interaction and in hippocampus, precuneus and retrosplenial cortex for sad social interaction. Individual differences in trait emotions and stable mood were measured with PANAS-X. For high fatigue participants greater activation was observed in the left amgydala for happy social interaction. For participants with high positive stable mood greater activation was observed in the insula for happy and sad social interaction. The research described here indicates that self-reported ethnic origin and mood are potentially significant influences on elicited emotion and brain reactivity to positive and negative social and emotional situations.

Attention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterized by increased hyperactivity, impulsivity, and inattention. Some theories propose that ADHD is caused by a deficit in inhibitory control, interacting with other executive functions (e.g., emotional control) to lead to behavioural dysfunction. Furthermore, certain brain regions have been found to be involved in executive functions, and several studies have examined the neural correlates of ADHD at broad-based levels. Increased interest has been placed on the Anterior Cingulate Cortex (ACC), which is known to play a role in attention and other complex cognitive processes. Thus, to further clarify the nature of the behavioural and cognitive deficits observed in ADHD, and to elucidate potential relationships between these difficulties and their neural substrates with more specificity, volumetric analyses of the ACC were conducted. For this purpose, 10 children with ADHD and 10 matched controls underwent magnetic resonance imaging and neuropsychological assessment. Manual tracing of ACC subregions was conducted using ANALYZE 9.0 (Mayo Clinic), followed by between-group statistical comparisons. Correlation analyses were used to investigate whether ACC subregions were associated with performance on executive functions tasks. It was hypothesized that there would be significant volumetric groups differences between the two groups, and that subregions would have a differential relationship with executive function performance. Results indicated the ADHD group has marginally larger right dorsal ACC volumes relative to controls. Further, between the two groups, brain-behaviour relationships were different. These results provide support for the hypothesis of a delay in neuronal maturation of the ACC in children with ADHD from Spain. / Graduate

Autism spectrum disorder (ASD) is considered a disease of neuronal dysfunction based on pathological alterations in axon thickness and neuronal disorganization. Recent findings suggest non-neuronal cells may also play a role in ASD brain pathology. White matter areas in the ASD brain display enlargement paired with a reduction in structural integrity. These structural abnormalities are likely associated with dysfunction of the most prevalent cell types present in white matter, astrocytes and oligodendrocytes. In fact, myelin abnormalities and structural changes of reactive astrocytes have been reported in ASD. The goal of the present study was to further investigate glia pathology in the white matter of the ASD brain. The primary brain area of interest was the anterior cingulate cortex (BA24) because this brain region mediates social interactive behavior, disruption of which is a core behavioral feature of ASD. Furthermore, a reduction in the structural integrity of white matter in BA24 has been observed in ASD. Postmortem brain tissues were obtained from highly characterized ASD and developmentally normal control donors. Quantitative Western blotting was used to measure glial fibrillary acidic protein (GFAP) and myelin oligodendrocyte glycoprotein (MOG) produced by astrocytes and oligodendrocytes, respectively. A significant elevation in levels of GFAP-immunoreactivity (p=0.005) in BA24 white matter was observed in ASD as compared to control donors. In contrast, levels of MOG-immunoreactivity in BA24 white matter were similar when comparing ASD to control donors. Levels of both GFAP and MOG in the BA24 gray matter from the same subjects were similar comparing the two groups of donors. Measurement of GFAP gene expression in BA24 white matter did not reveal any difference between ASD and control donors. To further examine the regional specificity of the observed glial pathology, we analyzed GFAP and MOG protein expression in the anterior prefrontal cortex (BA10) white matter. Levels of GFAP- and MOG-immunoreactivities were unchanged in BA10 white matter comparing ASD to control donors. These findings demonstrate that astrocytic pathology is both tissue-specific (white matter) and regionally selective (BA24) in ASD. Elevation of GFAP protein in BA24 white matter implies an activation of astrocytes possibly as a result of a yet undefined cellular insult. Research is needed to investigate the molecular pathways that underlie this astrocyte reaction and such research may yield important clues regarding the etiology of ASD.

The anterior cingulate cortex (ACC) expresses high density of Gastrin-releasing peptide (GRP) and GRP receptor mRNA. To address possible function, this investigation used patch clamp recordings in mouse brain slice preparations to evaluate intrinsic properties of ACC neurons and neuronal responses to bath-applied GRP peptide. The ACC neurons were divided according to their morphology, the properties of action potentials and their firing pattern in response to depolarizing current pulses. Two physiological groups of interneurons and three groups of pyramidal neurons were defined. Application of the GRP induced depolarization and increased firing of the interneurons while hyperpolarization and reduced firing in pyramidal neurons. Moreover, activation of GRP receptor facilitated GABAergic neurotransmission via a postsynaptic mechanism. The results suggest that GRP receptor is an important regulator of neuronal circuits in the ACC and may consequently play an important role for ACC neurons in the central processing of high brain function.

The anterior cingulate cortex (ACC) expresses high density of Gastrin-releasing peptide (GRP) and GRP receptor mRNA. To address possible function, this investigation used patch clamp recordings in mouse brain slice preparations to evaluate intrinsic properties of ACC neurons and neuronal responses to bath-applied GRP peptide. The ACC neurons were divided according to their morphology, the properties of action potentials and their firing pattern in response to depolarizing current pulses. Two physiological groups of interneurons and three groups of pyramidal neurons were defined. Application of the GRP induced depolarization and increased firing of the interneurons while hyperpolarization and reduced firing in pyramidal neurons. Moreover, activation of GRP receptor facilitated GABAergic neurotransmission via a postsynaptic mechanism. The results suggest that GRP receptor is an important regulator of neuronal circuits in the ACC and may consequently play an important role for ACC neurons in the central processing of high brain function.

Temperament is thought to be the foundation for normative personality and subsequent behaviors later in life. To assess the relationship of early temperament with variation in structural brain development, this study examined rhesus macaque mother-infant behavior, and then three years later, used MRI to assess neurostructural differences. Individual differences in mother-infant interactions and emotionality were then linked to brain differences. Extensive behavioral data obtained over the first year of life under both resting and stressful conditions was used to assess the quality of mother-infant interactions and emotionality. The MRI focused on brain volume in areas thought to be related to emotional regulation and such as the cingulate gyrus and corpus callosum structures. These structures are often mentioned as areas that modulate emotions, temperament and general social behavior. The methods involved in this research include behavior coded from group-housed infant rhesus macaques (Macaca mulatta). The subjects were 15 mother-reared subjects, each housed in a social group of 12-20 subjects, living in social settings with their mothers, other adult females, two adult males, and other same-aged subjects; conditions that approximate the social composition of the natural setting. Behaviors related to temperament and mother-infant interactions were assessed using an objective behavioral scoring system. Behavior was coded under three conditions, and each behavioral coding session was 5-minute long. Homecage: Two behavioral coding sessions were recorded weekly for each subject as it interacted naturally with its mother and peers over the first six-months of life. Preseparation (month 6): Two weeks before four, sequential, 4-day social separations, behavioral data were collected once each day. Reunion with mother: Following each of the social separations, data were collected twice immediately following return to mother and again on the morning before the separation. Subjects underwent MRIs 1-2 years later when they were 2-3 years of age. The result of this research was that during pre-separation interactions, anterior cingulate size to brain ratio showed a positive correlation with mutual ventral contact (being cradled and held closely), a measure of the use of mother as a secure base to calm anxiety and fear.

Cognitive dissonance is the uncomfortable psychological feeling that arises when something is perceived as contradictory. In 1957, Leon Festinger first developed the theory of cognitive dissonance, which has since continued to be of interest for, among other things, decision-making, moral reasoning, motivation, politics, and science. This systematic review summarises six peer-reviewed studies that use functional magnetic resonance imaging (fMRI) to measure if there is increased activity in the anterior cingulate cortex (ACC) and dorsal anterior cingulate cortex (dACC) during cognitive dissonance in adults. Four studies tested cognitive dissonance during forced choices and two during counter-attitudinal behaviours. The overall fMRI results indicate increased activity in ACC and dACC to dissonance versus control conditions, but with some inconsistency on the exact locations in the brain.

Previous studies have reported altered glutamate (Glu) concentrations in the blood and brain of individuals with autism spectrum disorder (ASD) compared to neurotypical controls (NC), but the direction (increased or decreased) of metabolite differences is still unclear. Moreover, the relationship between Glu and both brain function and clinical manifestations of the disorder require further investigation. Within this study, we investigated metabolite concentrations within the dorsal anterior cingulate cortex (dACC), a brain region functionally associated with inhibitory executive control tasks and also part of the salience network. There were 19 participants with ASD and 20 NCs between the ages of 23 and 58 years who participated in this study. A study clinician administered the Autism Diagnostic Observation Schedule (ADOS) to individuals with ASD to further confirm their diagnosis. In addition, all participants in this study completed assessments of general intelligence and attention, which included an inhibitory executive control task. Researchers also acquired in vivo single-voxel proton magnetic resonance spectroscopy (1H-MRS) in the dACC to quantify both Glu and combined Glu and glutamine (Glx) concentrations. We hypothesised that these metabolite concentrations would be altered (decreased or increased) in adult participants with ASD compared to NCs and would correlate with inhibitory performance and ASD severity in individuals with ASD. Participants also underwent a resting-state functional magnetic resonance imaging (fMRI) scan to assess the relationship between functional connectivity and Glu and Glx concentrations. We also hypothesised that there would be an altered relationship between local Glu and Glx concentrations and seed-based functional connectivity in adults with ASD compared to NCs. There were no significant group differences in Glu or Glx concentrations between individuals with ASD and NCs. Furthermore, we did not find any relationship between metabolite concentrations and either inhibitory performance or clinical symptoms of the disorder. This evidence suggests that increased or decreased Glu and Glx concentrations were not a core marker of altered brain function in the dACC in this group of adult individuals with ASD. When individuals taking psychotropic medications were excluded from the analysis, there was a significant interaction between age and group for Glx concentrations. This evidence weakly suggests disease-specific variations in Glx concentrations over the lifespan of an individual with ASD. Nevertheless, this result did not survive correction for multiple comparisons and requires further replication. In our final experiment, we reported that Glu concentrations were negatively correlated with right and left dACC seed-based resting-state functional connectivity to the left medial temporal lobe only in individuals with ASD. We also reported an interaction between groups in the association between Glx concentrations and both left and right dACC functional connectivity to other salience network regions including the insular cortex. This evidence suggests that local Glu and Glx concentrations were incongruent with long-distance functional connectivity in individuals with ASD. This analysis was largely exploratory, but further investigation and replication of these relationships may further explain the pathophysiology of the disorder as well as provide a useful marker for therapeutic intervention.

This thesis introduces a new theoretical framework from which to view the factors that contribute to stuttering variability. The speech and monitoring interaction (SAMI) framework proposes that there are two systems that account for stuttering variability: the speech production system and the monitoring system. Each system has unique factors that modulate them. Within SAMI, the interaction of these two categories of factors is formalized in a mathematical equation. What is particularly novel about SAMI is the use of a mathematical equation to formalize the interaction between these systems and the specific proposal of the biological substrates of the monitoring system and its interaction with the speech system. The focus of this thesis is on the anticipation of stuttering, which is one of the factors from SAMI that modulates the monitoring system. The goals of the studies were to 1) characterize the degree to which people who stutter (PWS) anticipate stuttering and how accurately they can predict actual stuttering, 2) investigate the correlation between stuttering expectancy on words and the verbal response time to say those word in word naming tasks, and 3) make a qualitative comparison of the behavioral results and the results from a neural network model. Utilizing the SAMI framework it was hypothesized that stuttering expectancy would be positively correlated with the response time and the results from the simulations would qualitatively match the behavioral results. The key finding was that across the group of PWS, there was positive correlation between stuttering expectancy scores and relative reaction times on those words. The degree to which stuttering expectancy was correlated with reaction time within subjects was positively correlated with stuttering severity. A qualitative comparison showed a good fit in between results of the simulations and the behavioral study. This is the first study to show that the expectation of stuttering has an effect on fluent speech production, providing evidence that the anticipation of stuttering is not only correlated with moments of stuttering but may also be a contributing factor to stuttering. The model provides a means of hypothesizing and testing specific neural substrates associated with anticipation of stuttering and its effects on the speech production process.