The current study is the first to demonstrate that structural deficits in the Anterior Cingulate Cortex (ACC) of the human brain may play a role in reading ability. Recent imaging work has indicated that the ACC is activated by tasks involving modulation of the fronto-temporal networks during language processing tasks and may be involved in anticipatory reactions and response preparation during reading. This study investigated the relationship between ACC volumetric measurements and reading ability in a sample of 68 individuals nested within 24 families with and without reading disorders. This sample allowed for examination of the effect of the volume of the ACC on reading, while controlling for normally occurring fluctuations in the size of the ACC due to heredity and shared environment. Forty-five linear models were conducted in SPSS on all 68 participants using the brain measurements (ACC, ACC with Paracingulate (PaC), and Putamen, separately) as well as control variables (gender, FSIQ, family membership) as predictors of the outcomes variables related to reading achievement (GORT Passage, rate, and accuracy) and reading processes (CTOPP phonological awareness and rapid naming). The use of family membership as a random effect predictor together with the specific brain volume as a predictor allowed for the effect of family on reading outcomes to be accounted for while, explicitly accounting for any relationships that may exist between family and brain volume. Additional sets of measurements, with PaC, were included in the final analyses to address the inconsistent inclusion of this tertiary structure in earlier research. Finally, a control region (putamen) was included to rule out whole brain effects and improve the specificity of the findings. The most significant findings were that the results varied systematically with inclusion or exclusion of the PaC. Measurements including the PaC were statistically significant for reading achievement for the left side of the ACC as expected. However, for the ACC volume without PaC, it was the right side that was related to reading measures. Neither set of measurements of the ACC were predictive of group membership. The current study supported a role for the ACC in reading and suggests a standardized method for inclusion of the PaC in the volumetric analysis of the ACC. / text

<p>The visual world is full of potentially important information, but only a subset of the world can be evaluated at any time. An essential function of the central nervous system is to rapidly and adaptively select which stimuli warrant attention. Much of the time, attention is directed towards stimuli that are relevant for current goals. However, things that have proven important in an organisms' personal or evolutionary past effectively compete with goal-relevant targets for attention. In humans, one example of this attentional superset is faces: faces attract attention even when they are in competition with immediate goals. Using a combination of behavioral, pharmacological, and electrophysiological techniques in the rhesus macaque, I investigated the physiological, neurobiological, and evolutionary determinants of the attentional capture of faces. First, I show that the prioritization of faces is evolutionarily conserved in primates. Face distractors also capture attention in rhesus macaques, a species of old world monkey, successfully competing with task goals for limited attentional resources. Importantly, the same classes of faces have the greatest attentional effects in both monkeys and humans. Further, I describe behavioral evidence that subcortical systems contribute to the attentional salience of faces in this species, proving an initial characterization of the neural mechanisms that may mediate this effect. Next, I examine the interaction between pupil size and vigilance for faces. A focal increase in luminance has long been known to provoke pupil constriction, but here I show that the pupil response to a flashed distractor is proportional to the allocation of attention to that image. Pupil constriction may provide a novel implicit metric of stimulus attention. In particular, face images provoked greater pupil constriction than non-face images. Moreover, I also find that baseline pupil size is a strong predictor of distractor interference, suggesting that arousal may modulate social vigilance. Therefore, I next examined the activity of single neurons within dorsal anterior cingulate cortex (dACC), a region implicated in task performance across a wide variety of tasks, but which also has strong connections to subcortical neuromodulatory centers responsible for regulating arousal. I find that the dACC discriminates between social and nonsocial distractors, scales with distractor attention, and predicts adjustments in arousal and vigilance state on upcoming trials. This is consistent with a model in which dACC supports task performance through regulating arousal. Finally, I turn to oxytocin (OT), a neuromodulatory hormone released during affiliative social interactions that is also implicated in regulating arousal. Though typically thought to generally enhance social attention, I report multiple circumstances in which OT suppresses, rather than enhances, vigilance for faces. This suggests a mechanism through which affiliative social interactions can reduce social vigilance, permitting more relaxed social interactions. Together, these results highlight an evolutionarily conserved neural circuit important for the adaptive, contextual modulation of reflexive face attention, a behavior that is compromised in both anxiety disorders and autism.</p> / Dissertation

Antipsychotic drugs (typical and atypical) are used in the treatment of mental disorders such as schizophrenia. Typical antipsychotic drugs (such as haloperidol) specifically target dopamine D2 receptors and produce extrapyramidal side effects. Atypical antipsychotic drugs (such as risperidone and olanzapine) primarily target dopamine D2 and serotonin 5HT2A receptors and produce fewer extrapyramidal symptoms (EPS) than do the typical antipsychotic drugs at clinically effective doses (Meltzer and Nash, 1991). It has been proposed that the prefrontal cortex (a brain region implicated in the pathophysiology of schizophrenia) is the locus of antipsychotic drug action to improve cognitive dysfunction and negative symptoms of schizophrenia (Weinberger and Lipska, 1995; Jakab and Goldman-Rakic, 1998). Moreover, it is possible that the effects in the prefrontal cortex may contribute to the differences between typical and atypical antipsychotic drugs as well as differences among atypical antipsychotic drugs (Horacek et al., 2006). The core pathology associated with the dorsolateral prefrontal cortex includes reduced cerebral volume, increased ventricle size and deficits in neuronal morphology, including increased cell packing density, reduction in dendrites and its associated dendritic spines (Selemon and Goldman-Rakic, 1999). However, since most neuropathology data emerge from in vivo imaging and post-mortem studies of patients with schizophrenia, it is difficult to interpret and distinguish between findings that have an etiological or iatrogenic basis. Thus, the objective of the current study was to examine the effects of antipsychotic drugs, at therapeutically relevant concentrations, in a rat brain region that is homologous to that of the human dorsolateral prefrontal cortex. The hypothesis upon which this study was based is that haloperidol, risperidone and olanzapine (at 65 to 80% striatal dopamine D2 receptor occupancy) induce changes to pyramidal cell architecture in the rat anterior cingulate cortex (Vogt and Gabriel, 1993; Hoover and Vertes, 2007). This hypothesis was investigated by (a) determining doses that are within the therapeutic range (65 to 80% striatal dopamine D2 receptor occupancy) by measuring the occupancy of haloperidol, risperidone and olanzapine in the presence of 3H-raclopride ( a dopamine D2 receptor antagonist) at dopamine D2 receptors in the rat striatum; and (b) examining whether therapeutic doses of antipsychotic drugs in rats cause neuropathology comparable to that observed in human post-mortem brains of patients with schizophrenia. Antipsyhcotic drug doses were selected using an appropriate in vivo dopamine D2 receptor occupancy method. The findings from this study revealed that 0.25 mg/kg/day haloperidol, 5 mg/kg/day risperidone and 10 mg/kg/day olanzapine achieved therapeutically relevant rat striatal dopamine D2 receptor occupancy in the range of 65 to 80%. To determine whether antipsychotic drugs at therapeutic doses established above induce changes in neuronal cell density and morphology; immunohistochemistry, single cell injection of lucifer yellow dye and Golgi-Cox impregnation of layer II/III pyramidal cells was performed. The results from these experiments revealed that the density of cells expressing NeuN, parvalbumin, calretinin or calbindin is highly unlikely to be affected by chronic exposure to haloperidol, risperidone and olanzapine. The current study evaluated the effects of chronic antipsychotic drug exposure on spontaneous locomotor activity of a rat in a novel environment. The purpose of this study was to differentiate between a direct and an indirect drug effect. It was found that at the doses established above, risperidone and olanzapine did not overtly reduce spontaneous locomotor activity of a rat in a novel environment relative to controls. In contrast, haloperidol reduced spontaneous locomotor activity of rat in an open field, although this was not statistically significant. Nevertheless, the data reported here allowed us to conclude that the level of activity across groups is unlikely to affect the data obtained in subsequent studies investigating the effects of chronic antipsychotic drug treatment on pyramidal cell structure. Intracellular injection of lucifer yellow dye into pyramidal cells revealed that chronic haloperidol treatment (28 days) was associated with a relative increase in basal dendritic arborisation, but neither of these drug treatments induced changes in arborisation that were different from controls. No statistically significant change in the basal dendritic arbor was detected with animals treated with risperidone relative to controls. Similarly using the Golgi-impregnation method, changes in soma size, dendritic branching, total number of branches and the density of dendritic spines in antipsychotic drug treated groups were not significantly different to controls. Taken together, this finding indicates that only relatively subtle neuritic changes may be attributed to chronic treatment with typical or atypical antipsychotic drugs administered at doses that avhieved striatal dopamine D2 receptor occupancy in the range of 65 to 80%. In summary, this study confirms that antipsychotic drugs are unlikely to induce changes to neuronal cell density or morphology in the rat anterior cingulate cortex at therapeutically relevant doses. Hence, it can be concluded that the observed neuropathology, found in the brains of patients with schizophrenia that have undergone antipsychotic drug therapy, is more likely to be caused by the disease and not the effects of the concomitant drug therapy.

Complicated grief, or persistent complex bereavement disorder, is a condition that affects approximately 10% of bereaved individuals and is marked by intense longing and yearning for the deceased. Little is known about the neurocognitive mechanisms contributing to this syndrome, but previous research suggests that reward pathways in the brain may play a role. The present study was designed with this theory in mind, aiming to understand reward processing in those experiencing complicated and non-complicated grief as well as to differentiate the "wanting" and "liking" phases of reward processing in bereavement. Twenty-five older adults were categorized based on grief severity into one of three groups: complicated grief (CG), non-complicated grief (NCG) and non-bereaved married controls (NB). Neural activation was examined using fMRI while participants viewed a countdown on the screen (anticipation) followed by a photo of their (living or deceased) spouse. There was no significantly differential activation between the three groups for the spouse v. stranger photo contrast, nor for anticipation period v. spouse photo. However, these two contrasts were also run separately in the three groups. Each group produced significant activation, in similar and distinct regions, primarily associated with emotion and visual processing. In addition, post-hoc analyses were conducted using self-reported yearning scores as a regressor across all bereaved participants, which revealed that greater symptoms of yearning predicted greater activation in the subgenual anterior cingulate cortex (sgACC). This region of the brain has been previously linked to depression and suggests that symptoms of yearning may present an opportune place to intervene to improve outcomes in CG.

The anterior cingulate cortex (ACC) is part of the cognitive and emotional brain circuitry that mediates social interaction. Imbalances between inhibitory, GABAergic neurons, and excitatory, glutamatergic neurons, in this region are essential to brain circuity during social responses and are thought to be involved with behaviors associated with autism spectrum disorder (ASD). Enriched cell populations of glutamatergic neurons, obtained through laser capture microdissection, were used for gene expression studies of GABAergic receptors (GABRA1, GABRA4, and GABBR1). Additionally, proteins that impact GABAergic synapses (Spinophilin, CPLX1, mTOR, IGF1R, PSD95, PARP1) were investigated using Western Blotting with punchdissected homogenate brain tissue from ACC and frontal cortical brain regions. No significant differences in gene expression nor protein were identified between ASD and control brain donors. Evidence of GABAergic synaptic pathology was not found; however, future studies of alternative GABAergic markers and increased study numbers are needed to confirm these findings in ASD human tissue.

Background: Altered brain morphology was one of the first pathobiological findings associated with autism spectrum disorder. These gross abnormalities, documented in both white and gray matter areas in autistic brains, are postulated to contribute to disrupted neuronal communication. For example, glutamatergic pyramidal neurons in the anterior cingulate cortex (ACC) have decreased size and increased cell density in autism. Objectives: We sought to determine whether autism-related gene expression abnormalities exist in the ACC that might underlie previously observed cell morphological alterations found in this brain region. Specifically, levels of expression of genes associated with glutamatergic neurotransmission were measured in pyramidal neurons and surrounding astrocytes in the ACC of postmortem brain tissues from autism donors and matched developmentally normal control donors. Methods: Postmortem brain tissues were obtained from 6-8 age-matched pairs of male subjects who had autism and developmentally normal control males (age range 6-37). Laser-guided microdissection was used to capture pure populations of pyramidal neurons and astrocytes from layer III of the ACC. The expression of glutamate-related genes was measured in RNA isolates by reverse transcription followed by end-point PCR using three stable reference genes to normalize expression levels. Results: ACC pyramidal neurons from autism subjects demonstrated significantly reduced gene expressions of the obligatory glutamatergic NMDA receptor subunit NR1, a glutamate transporter SLC1A1, and the glutamate receptor anchoring protein GRIP1. There was also a robust reduction in the gene expression of the brain-derived neurotrophic factor (BDNF) receptor NTRK2 in autism pyramidal neurons, with gene expression levels of BDNF itself unaffected. No gene expression abnormalities were observed in ACC astrocytes surrounding the pyramidal neurons from autistic subjects. Conclusions: Autism spectrum disorder is associated with a reduction in the expression of genes associated with glutamatergic neurotransmission and downstream BDNF signaling in pyramidal neurons of the ACC. These findings suggest that glutamatergic signaling is compromised in these excitatory neurons in autism and raise hope that drugs or other treatments may be developed to overcome these pathobiological deficits.

A hallmark of higher-order cortical regions is their functional heterogeneity, but it is not well understood how these areas are able to encode diverse behavioral information. The anterior cingulate cortex (ACC), for example, is known to be important in a large range of behaviors, including, decision making, emotional regulation and social cognition. In support of this, previous work shows activation of the ACC to anxiety-related and social stimuli but does not use cellular resolution or cell-type specific techniques to elucidate the possible heterogeneity of its subcircuits. In this work, I investigate how subpopulations of neurons or microcircuits within the ACC encode these different kinds of stimuli. One type of inhibitory interneuron, which is positive for vasoactive intestinal peptide (VIP), is known to alter the activity of clusters of pyramidal excitatory neurons, often by inhibiting other types of inhibitory cells. Prior to this research, it was unknown whether the activity of VIP cells in the ACC (VIPACC) encodes anxiety-related or social information and whether all VIPACC activate similarly to the same behavioral stimuli. Using in vivo Ca2+ imaging and 3D-printed miniscopes in freely behaving mice to monitor VIPACC activity, I have identified distinct subpopulations of VIPACC that preferentially activate to either anxiogenic, anxiolytic, social, or non-social stimuli. I also demonstrate that these stimulus-selective subpopulations are largely non-overlapping and that clusters of cells may co-activate, improving their encoding. Finally, I used trans-synaptic tracing to map monosynaptic inputs to VIP and other interneuron subtypes in the ACC. I found that VIPACC receive widespread inputs from regions implicated in emotional regulation and social cognition and that some inputs differ between types of ACC interneurons. Overall, these data demonstrate that the ACC is not homogeneous – there is marked functional heterogeneity within one interneuron population in the ACC and connective heterogeneity across ACC cell types. This work contributes to our broader understanding of how the cortex encodes information across diverse contexts and provides insight into the complexity of neural processes involved in anxiety and social behavior.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24842号 / 医博第5010号 / 新制||医||1068(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙橋, 良輔, 教授 林, 康紀, 教授 井上, 治久 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Bakgrund: Smärta definieras som en subjektiv upplevelse där upplevelsen till viss del formas i hjärnan genom komplexa processer. Långvarig stress har visat sig leda till förändring i smärtkänsligheten vilket kanske förklaras av att akut stress förändrar aktivitet i främre delar av hjärnan. Anterior cingulate cortex (ACC) är ett frontalt hjärnområde med en roll i den emotionella upplevelsen av smärta. Det finns indikationer på förändringar i ACC av den hämmande transmittorsubstansen GABA, och den stimulerande transmittorsubstansen glutamat, vid vissa smärttillstånd.  Motiv: I dagsläget saknas kunskap om hur stress påverkar smärtkänslighet samt hur det påverkar grundnivåerna av transmittorsubstanserna GABA och glutamat.  Syfte: Att studera samband mellan skattad stress och skattad smärta, samt studera samband mellan skattad stress, smärta, GABA och glutamat i två ACC regioner.  Metod: En experimentell pilotstudie med kvantitativ design utfördes med 10 friska deltagare. Percieved Stress Questionnaire användes för skattning av stressnivåer före smärtprovokation och Numeric Rating Scale användes för att skatta smärta vid smärtprovokation. GABA- och glutamatnivåer i två ACC regioner mättes med hjälp av Magnetic Resonans Spectroscopi.  Resultat: Spearmans test visade att det fanns ett signifikant positivt samband mellan skattad stress och skattad smärta (r=.86, p=.001). Det fanns även signifikant positivt samband mellan skattad stress och glutamat (r=.778, p=.008), skattad smärta och glutamat (r=.729, p=.017). Samt ett signifikant negativt samband mellan skattad stress och GABA (r= -.687, p=.028), skattad smärta och GABA (r=-.667, p=.035) i två ACC regioner.  Konklusion: Resultatet indikerar att sambandet mellan stress och smärta kan förklaras av förändringar i transmittorsubstansnivåer i två ACC regioner. Denna kunskap kan bidra till ökad förståelse hos vårdpersonalen för individuella skillnader i smärtkänslighet och hur komplex situationen kring patienter med smärta är, vilket motiverar till omvårdnadsåtgärder som minskar stress och smärta. / Background: Pain is defined as a subjective experience that some extent is formed through complex processes in the brain. Prolonged stress can affect pain sensitivity, which may be explained by changes in frontal parts of the brain. The anterior cingulate cortex (ACC) is a frontal brain area that plays a role in the emotional experience of pain. In certain pain conditions, there are indications of changes in the neurotransmitter level GABA and glutamate in ACC. Motive: At present, there is a lack of knowledge about how stress affects pain sensitivity and how it affects the basic levels of the neurotransmitter GABA and glutamate in ACC.  Aim: To study the correlation between rated stress and pain, and study the correlation between rated stress, pain, GABA, and glutamate in ACC.  Methods: An experimental pilot study was performed with 10 healthy participants. The Perceived Stress Questionnaire was used to rate stress levels before pain provocation and the Numeric Rating Scale was used to rate pain during pain provocation. GABA and glutamate levels were measured in ACC by Magnetic Resonance Spectroscopy.  Result: Spearman´s test showed a significant positive correlation between rated stress and rated pain (r = .86, p = .001). There was a significant positive relationship between rated stress and glutamate (r = .778, p = .008), rated pain and glutamate (r = .729, p = .017) and a significant negative correlation between rated stress and GABA (r = -.687, p = .028), rated pain and GABA (r = -.667, p = .035) in ACC.  Conclusion: The results indicate that the correlation between stress and pain can be explained by changes in transmitter levels in the ACC region. This knowledge can contribute to increased understanding among healthcare professionals for individual differences in pain sensitivity and the complexity of pain conditions.

We humans depend heavily on cognitive control to make decision and execute goal-directed behaviors, without which our behavior would be overpowered by automatic, stimulus-driven responses. In my dissertation, I focus on a brain region most implicated in this crucial process: the anterior cingulate cortex (ACC). The importance of this region is highlighted by lesion studies demonstrating diminished self-initiated behavior, or apathy, following ACC damage, the most severe form of which results in the near complete absence of speech production and willed actions in the presence of intact motor ability. Despite decades of research, however, its precise function is still highly debated, due particularly to ACC’s observed involvement in multiple aspects of cognition. In my dissertation I examine ACC function according to recent developments in reinforcement learning theory that posit a key role for ACC in motivating extended behavior. According to this theory, ACC is responsible for learning task values and motivating effortful control over extended behaviors based on those learned task values. The aim of my dissertation is two-fold: 1) to improve understanding of ACC function, and 2) to elucidate the contribution of ACC to depression, as revealed by individual differences in several personality traits related to motivation and reward sensitivity in a population of healthy college students. It was hypothesized that these different personality traits express, to greater or lesser degrees across individuals, ACC function, and that their abnormal expression (in particular, atypically low motivation and reward sensitivity) constitute hallmark characteristics of depression. First, this dissertation reveals that reward positivity (RewP), a key electrophysiological signature of reward processing that is believed to index the impact of reinforcement learning signals carried by the midbrain dopamine system on to ACC, is sensitive to individual differences in reward valuation, being larger for those high in reward sensitivity and smaller for those high in depression scores. Second, consistent with a previous suggestion that people high in depression or depression scores have difficulty using reward information to motivate behavior, I find these individuals to exhibit relatively poor prolonged task performance despite an apparently greater investment of cognitive control, and a reduced willingness to expend effort to obtain probable rewards, a behavior that was stable with time on task. In contrast, individuals characterized by high persistence, which is indicative of good ACC function, exhibited high self-reported task engagement and increasing effortful behaviors with time on task, particularly for trials in which reward receipt was unlikely, suggesting increased motivational control. In sum, this dissertation emphasizes the importance of understanding the basic function of ACC as assessed by individual differences in personality, which is then used to understand the impact of its dysfunction in relation to mental illnesses. / Graduate