This study examined the cumulative, more insidious, impact of repeated drinking on sober-state aggression based on research that has pointed to the negative neural effects of chronic alcohol consumption, especially on frontal lobe functioning. In particular, it examined the relationship between repeated alcohol use and sober-state reactive aggression as it is mediated or moderated by sober-state executive cognitive functioning (ECF), thus expanding upon research that has examined the relationship between acute alcohol intoxication and consequent aggression while under the influence (Giancola, 2000b). It was hypothesized that ECF would mediate the relationship between repeated alcohol use and sober-state reactive aggression in college students in that a history of alcohol use would lower sober-state ECF which in turn would increase sober-state impulsive aggression in individuals. It was further hypothesized with a moderational model that high levels of ECF would offset the more insidious effects of repeated alcohol use on subsequent sober-state aggressive acts. Moreover, those effects would remain after controlling for potential confounds of violence exposure, gender, and intelligence. Eighty college students, aged 18-23 years, from Virginia Tech were recruited to participate in this study. A self-report measure for aggression, neuropsychological tests for ECF, and a lifetime drinking interview schedule were used to assess the relationship between cumulative alcohol use, sober ECF, and sober aggression. A combination of bivariate and hierarchical regression analyses was used to analyze the data. The hypotheses of this study were not supported. Instead, the results supported a positive relationship between prior exposure to violence and later escalation of alcohol use and perpetrated violence. Additionally, these results support the presence of a "binge drinking" pattern within the sample. / Master of Science

Individuals with attention deficit hyperactivity disorder (ADHD) with and without a learning disorder (LD) and a control group of clinically referred individuals with behavioral problems were compared on four neuropsychological tests of frontal lobe functioning. Test results were collected to examine if ADHD individuals with and without LD have deficits in frontal lobe functioning. Two age groups were used to examine developmental differences. In the six to ten age group there were 27 ADHD, 17 ADHD/LD and seven other clinically referred individuals. In the 11 -20 age group there were 12 ADHD, 23 ADHD/LD and 24 other clinically referred individuals. The ADHD and ADHD/LD groups performed at a lower level than the other diagnostic group on the freedom from distractibility factor of the WISC-R and the omission and commission errors of the Gordon Diagnostic system. Differences for the ADHD and ADHD/LD groups were also found on the number of correct responses for the Gordon Diagnostic system, the Speech Sounds test and the Seashore Rhythm test. The developmental differences that were found were not influenced by diagnosis. The deficits that the ADHD individuals with and without LD demonstrated were not affected by age.

A lobectomia frontal é um procedimento neurocirúrgico frequentemente realizado para o tratamento de tumores cerebrais, epilepsia refratária, e outras patologias que requerem remoção extensa do lobo frontal. Embora seja um procedimento relativamente comum, foram encontrados apenas alguns relatos na literatura acerca da técnica cirúrgica, com pouca consideração acerca da anatomia relevante para esse procedimento. OBJETIVOS: O principal objetivo desta tese é apresentar parâmetros anatômicos e considerações técnicas para a remoção da substância cinzenta do lobo frontal (decorticação do lobo frontal) como uma alternativa a lobectomia frontal. A finalidade deste estudo é a maximização da remoção cerebral, diminuindo a perda sanguínea, e evitando a abertura do corno frontal do ventrículo lateral. MATERIAIS E MÉTODOS: O estudo anatômico foi realizado em 15 cabeças cadavéricas adultas. Os dados clínicos foram baseados em 15 decorticações frontais realizadas de 2002 a 2014. RESULTADOS: A decorticação frontal envolve as superfícies lateral, medial e basal, e consiste em 5 passos principais: a) coagulação e secção dos ramos arteriais da superfície lateral do lobo frontal; b) ressecção subpial paramediana do lobo frontal até a localização do joelho do corpo caloso; c) ressecção da substância cinzenta da superfície lateral do lobo frontal sem entrar no corno frontal; d) identificação e preservação do trato olfatório; e) remoção da substância cinzenta da superfície basal do lobo frontal. Esta técnica cirúrgica foi aplicada em 15 casos, em nenhum deles o corno frontal do ventrículo lateral foi aberto, evitando complicações da abertura do mesmo. CONCLUSÃO: A decorticação frontal guiada por parâmetros anatômicos pode ser uma das técnicas cirúrgicas a ser considerada quando há necessidade da ressecação extensa do lobo frontal (especialmente substância cinzenta). A técnica proporciona máxima remoção do lobo frontal, preservação do corno frontal e da área motora suplementar, e redução da perda sanguínea / BACKGROUND: The frontal lobectomy is a frequently performed neurosurgical procedure for treating brain tumors, refractory epilepsy, and other disorders that require extensive removal of the frontal lobe. In spite of being a relatively common procedure, there are only few reports available regarding its surgical technique and little attention has been given to the anatomy relevant to this procedure. OBJECTIVES: The authors present the anatomical landmarks and technical nuances for removing the gray matter of the frontal lobe (frontal lobe decortication) as an alternative to frontal lobectomy. The goals are to maximize the brain removal, minimize the blood loss, and avoid opening the frontal horn of the lateral ventricle. MATERIAL AND METHODS: The anatomical study was performed in 15 adult cadaveric heads. The clinical data are based on 15 frontal resections performed from 2002 to 2014. RESULT: The frontal decortication involves the lateral, medial, and basal surfaces of the frontal lobe, and it consists of 5 main steps: a) coagulation and section of the arterial branches of the lateral surface of the frontal lobe; b) paramedian subpial resection of the frontal lobe until the genu of the corpus callosum is located; c) resection of the gray matter of the lateral surface of the frontal lobe without entering the frontal horn; d) identification and preservation of the olfactory tract; e) removal of the gray matter of the basal surface of the frontal lobe. This surgical technique was applied in 15 cases, and it was possible to preserve the frontal horn in all the patients when following this technique, avoiding complications resulted by its opening. CONCLUSION: The frontal decortication guided by intraoperative anatomical landmarks can be one of the surgical techniques to be considered when an extensive frontal lobe resection (especially gray matter) is needed. It offers maximum frontal lobe removal, preservation of the frontal horn and supplementary motor area, and reduced blood loss

Prenatal maternal stress and mood, and early postnatal mother-infant interactions set the stage for the child’s psychobiological, neurological and social development. While a large body of research connecting maternal depression to infant EEG asymmetry exists, the current study sought to add to the sparse literature on maternal anxiety and infant EEG. Mother-infant dyads were assessed prenatally during the third trimester, soon after birth, at 6 weeks and 3 months postnatal. Association between maternal depression and later development of right mid-frontal alpha asymmetry was confirmed, while trends suggested maternal anxiety may be associated with lateral frontal alpha asymmetry. Greater maternal sensitivity and anxiety were each associated with lower post-stressor cortisol in infants with right frontal asymmetry. Greater time spent in mutual gaze was associated with positive infant affect. Finally, quality mother-infant dynamics encourage positive infant affect and healthy physiological stress regulation even when brain patterns associated with dysregulation have been established. / Includes bibliography. / Thesis (M.A.)--Florida Atlantic University, 2017. / FAU Electronic Theses and Dissertations Collection

Executive functioning is a multidimensional concept encompassing higher-order adaptive abilities, such as judgment, decision-making, self-monitoring, planning, and emotional regulation. Disruption in executive functioning often results in devastating impairments in vitally-important areas of life, such as one's ability to hold employment and maintain social relationships. Executive functions have been associated primarily with the prefrontal cortex. However, the nature and degree of the association between frontal lobe damage and performance on executive functioning tests remains controversial. Research suggests that the association may vary based on the specific location of damage within the prefrontal cortex, as well as the used measure of executive functioning. Few investigations have systematically addressed these variables. The current study employed the lesion method to investigate the relationship between performance on a battery of executive functioning tests and damage to specific regions of the prefrontal cortex. Three groups of participants with lesions in one of the locations of interest [ventromedial prefrontal (VMPC, n = 14), dorsolateral prefrontal (DLPC, n = 14), and non-frontal (n = 18)] were administered the Delis-Kaplan Executive Function System (D-KEFS, 2001), a comprehensive battery of executive functioning tests. Results revealed no statistically-significant differences between group performances on the D-KEFS primary measures. However, a qualitative analysis of the results revealed several meaningful group differences. It appears that some relationship exists between frontal lobe damage, particularly in the DLPC, and decreased performance on several executive functioning tests but further research overcoming the methodological limitations of most existing literature on this topic is needed to clearly resolve this issue.

This study was conducted to investigate the processes underlying the relation between executive functioning and false belief knowledge. We explored the hypothesis that children with advanced executive functioning skills are better equipped to capitalize on the experiences that are necessary to learn how to reason about others’ mental states. To examine this possibility, we recruited 3.5-year-old children with age-appropriate variability in executive functioning skills to participate in a training study designed to promote their performance on false belief tasks. We found that individual differences in executive functioning task scores strongly and consistently predicted the extent to which children benefited from false-belief training. Importantly, the relation between executive functioning and false belief improvement remained significant after controlling for age, initial performance on mental state reasoning tasks, language skills, and executive functioning improvement across the testing period. Thus, our results support the hypothesis that executive functioning skills influence the extent to which children are able to capitalize on relevant experience to better predict and understand others’ false-belief-based behaviour. This claim is discussed with respect to possible alternative explanations for our findings, and ensuing implications for understanding the interplay between neuromaturational factors and experience. / Thesis (Master, Psychology) -- Queen's University, 2007-09-28 14:43:16.88

Background: Patients with non-penetrating traumatic brain injuries (TBI) are at high risk for damage to ventral prefrontal brain regions, due to the brain’s acceleration into the bony ridges of the anterior portions of the skull. Current neuropsychological assessments of these patients focus mainly on the assessment of so-called “executive functions,” which are associated with dorsolateral prefrontal regions. Ventral prefrontal pathology is more likely to disrupt social and emotional functions, but assessments of these abilities using objective measurements that require patients to demonstrate their competence are rare. Mounting evidence suggests that chronic social and emotional deficits are common in TBI, and that these difficulties result in significant functional impairments post-injury, making clear the need to develop and use objective assessment tools during clinical neuropsychological assessments. Methods: In the current project, the Global Interpersonal Skills Test (GIST), a questionnaire measure of social skills with both a self-rated and an informant-rated version, was developed, along with three novel or adapted performance-based measures of social and emotional functioning. The first novel measure was the Assessments of Social Context (ASC), a video-based task examining comprehension of social context using non-verbal cues, including the identification of emotions, intensions and positive or negative attitudes of one person towards another. The second task was the Awareness of Interoception Test (AIT), a heartbeat detection paradigm adapted from previous literature that measures participants’ sensitivity to their cardiac function, which is implicated in basic emotional functioning. The third task was the Social Interpretations Task (SIT), an animation-based task adapted from previous literature examining participants’ ability to apply a social interpretation to stimuli that are not inherently social in nature. All novel tasks were developed and piloted with healthy undergraduates. A group of patients with moderate to severe TBI (N = 16), and a group of non-brain damaged controls (N = 16) underwent neuropsychological testing. Standard neuropsychological measures including the Wechsler Test of Adult Reading, Digit Span and Digit Symbol Coding from the Wechsler Adult Intelligence Scale, phonemic (FAS) and semantic fluency (Animals) from the Verbal Fluency Test, and the Trail Making Test, as well as the novel measures to both patients with TBI and controls were administered. The following predictions were made: vi 1) The novel performance-based measures of social abilities would be more sensitive to the presence of moderate and severe TBI than the standard neuropsychological measures of cognition; 2) On the informant version of the GIST, but not the self-report version, patients would have scores than controls; 3) Patients’ performance on the ASC would be less accurate than controls’, and this difference would be associated with real-world social skills, measured by the informant-version of the GIST; 4) Patients’ AIT performance would be less accurate than controls’, and this would be related to their self-rated emotional changes; 5) Patients’ SIT performance would be less accurate than controls’, and this difference would be associated with real-world social skills, again measured by the informant-version of the GIST. Findings: Findings were consistent with these hypotheses: 1) A statistically significant logistic regression revealed that a Social composite variable comprising the ASC, AIT and SIT was more sensitive to the presence of TBI (β = 9.59, p < .05) than a Cognitive composite variable comprising Digit Symbol Coding, Trails B completion time, and Phonemic Fluency (β = 0.006, p = .466). 2) A multivariate analysis of variance (MANOVA) revealed that informants of patients gave lower GIST scores to patients than the informants of controls (F(1,28) = 22.2, p < 0.0001), whereas there were no differences between groups on the self-rated version of the GIST (F(1,28) = .35, p = .56); 3) Patients’ ASC performance was significantly poorer than controls’ on a MANOVA (F(1,31) = 21.7, p < .0001), and ASC total scores were significantly correlated with GIST informant scores, using Spearman’s rank-order correlations (ρ(31) = .624, p < .0001). 4) Patients’ AIT performance was significantly poorer than controls’ using an independent samples t test (t(13) = 1.43, p < 0.005), and qualitative investigation of subjective reports of emotional change among patients suggested a potential relationship between emotional changes and AIT performance. vii 5) Patients’ SIT performance was significantly poorer than controls on an independent samples t test (t(30) = -2.12, p < 0.05), and SIT scores were significantly correlated with GIST informant scores, using Spearman’s rank-order correlations (ρ(31) = .460, p < .0001). Interpretation: This research represents a preliminary step in the development of clinically useful measures of social and emotional difficulties following TBI. Given the small sample size of the patient group, and the presence of co-morbid difficulties among some of the participants in this research, further testing of these measures in larger, more homogeneous samples would strengthen the current results, as would using a comparison group of people with milder TBI, rather than neuro-typical controls. The complexity of social behaviour requires that the current measures be further validated against other real-world assessments of social ability, and that assessments of other aspects of social behaviour be conducted. Nonetheless, the measures described here are a promising start to supplementing the neuropsychological toolkit in an area that requires further development at the present time.

Background: Patients with non-penetrating traumatic brain injuries (TBI) are at high risk for damage to ventral prefrontal brain regions, due to the brain’s acceleration into the bony ridges of the anterior portions of the skull. Current neuropsychological assessments of these patients focus mainly on the assessment of so-called “executive functions,” which are associated with dorsolateral prefrontal regions. Ventral prefrontal pathology is more likely to disrupt social and emotional functions, but assessments of these abilities using objective measurements that require patients to demonstrate their competence are rare. Mounting evidence suggests that chronic social and emotional deficits are common in TBI, and that these difficulties result in significant functional impairments post-injury, making clear the need to develop and use objective assessment tools during clinical neuropsychological assessments. Methods: In the current project, the Global Interpersonal Skills Test (GIST), a questionnaire measure of social skills with both a self-rated and an informant-rated version, was developed, along with three novel or adapted performance-based measures of social and emotional functioning. The first novel measure was the Assessments of Social Context (ASC), a video-based task examining comprehension of social context using non-verbal cues, including the identification of emotions, intensions and positive or negative attitudes of one person towards another. The second task was the Awareness of Interoception Test (AIT), a heartbeat detection paradigm adapted from previous literature that measures participants’ sensitivity to their cardiac function, which is implicated in basic emotional functioning. The third task was the Social Interpretations Task (SIT), an animation-based task adapted from previous literature examining participants’ ability to apply a social interpretation to stimuli that are not inherently social in nature. All novel tasks were developed and piloted with healthy undergraduates. A group of patients with moderate to severe TBI (N = 16), and a group of non-brain damaged controls (N = 16) underwent neuropsychological testing. Standard neuropsychological measures including the Wechsler Test of Adult Reading, Digit Span and Digit Symbol Coding from the Wechsler Adult Intelligence Scale, phonemic (FAS) and semantic fluency (Animals) from the Verbal Fluency Test, and the Trail Making Test, as well as the novel measures to both patients with TBI and controls were administered. The following predictions were made: vi 1) The novel performance-based measures of social abilities would be more sensitive to the presence of moderate and severe TBI than the standard neuropsychological measures of cognition; 2) On the informant version of the GIST, but not the self-report version, patients would have scores than controls; 3) Patients’ performance on the ASC would be less accurate than controls’, and this difference would be associated with real-world social skills, measured by the informant-version of the GIST; 4) Patients’ AIT performance would be less accurate than controls’, and this would be related to their self-rated emotional changes; 5) Patients’ SIT performance would be less accurate than controls’, and this difference would be associated with real-world social skills, again measured by the informant-version of the GIST. Findings: Findings were consistent with these hypotheses: 1) A statistically significant logistic regression revealed that a Social composite variable comprising the ASC, AIT and SIT was more sensitive to the presence of TBI (β = 9.59, p < .05) than a Cognitive composite variable comprising Digit Symbol Coding, Trails B completion time, and Phonemic Fluency (β = 0.006, p = .466). 2) A multivariate analysis of variance (MANOVA) revealed that informants of patients gave lower GIST scores to patients than the informants of controls (F(1,28) = 22.2, p < 0.0001), whereas there were no differences between groups on the self-rated version of the GIST (F(1,28) = .35, p = .56); 3) Patients’ ASC performance was significantly poorer than controls’ on a MANOVA (F(1,31) = 21.7, p < .0001), and ASC total scores were significantly correlated with GIST informant scores, using Spearman’s rank-order correlations (ρ(31) = .624, p < .0001). 4) Patients’ AIT performance was significantly poorer than controls’ using an independent samples t test (t(13) = 1.43, p < 0.005), and qualitative investigation of subjective reports of emotional change among patients suggested a potential relationship between emotional changes and AIT performance. vii 5) Patients’ SIT performance was significantly poorer than controls on an independent samples t test (t(30) = -2.12, p < 0.05), and SIT scores were significantly correlated with GIST informant scores, using Spearman’s rank-order correlations (ρ(31) = .460, p < .0001). Interpretation: This research represents a preliminary step in the development of clinically useful measures of social and emotional difficulties following TBI. Given the small sample size of the patient group, and the presence of co-morbid difficulties among some of the participants in this research, further testing of these measures in larger, more homogeneous samples would strengthen the current results, as would using a comparison group of people with milder TBI, rather than neuro-typical controls. The complexity of social behaviour requires that the current measures be further validated against other real-world assessments of social ability, and that assessments of other aspects of social behaviour be conducted. Nonetheless, the measures described here are a promising start to supplementing the neuropsychological toolkit in an area that requires further development at the present time.

Background: Patients with non-penetrating traumatic brain injuries (TBI) are at high risk for damage to ventral prefrontal brain regions, due to the brain’s acceleration into the bony ridges of the anterior portions of the skull. Current neuropsychological assessments of these patients focus mainly on the assessment of so-called “executive functions,” which are associated with dorsolateral prefrontal regions. Ventral prefrontal pathology is more likely to disrupt social and emotional functions, but assessments of these abilities using objective measurements that require patients to demonstrate their competence are rare. Mounting evidence suggests that chronic social and emotional deficits are common in TBI, and that these difficulties result in significant functional impairments post-injury, making clear the need to develop and use objective assessment tools during clinical neuropsychological assessments. Methods: In the current project, the Global Interpersonal Skills Test (GIST), a questionnaire measure of social skills with both a self-rated and an informant-rated version, was developed, along with three novel or adapted performance-based measures of social and emotional functioning. The first novel measure was the Assessments of Social Context (ASC), a video-based task examining comprehension of social context using non-verbal cues, including the identification of emotions, intensions and positive or negative attitudes of one person towards another. The second task was the Awareness of Interoception Test (AIT), a heartbeat detection paradigm adapted from previous literature that measures participants’ sensitivity to their cardiac function, which is implicated in basic emotional functioning. The third task was the Social Interpretations Task (SIT), an animation-based task adapted from previous literature examining participants’ ability to apply a social interpretation to stimuli that are not inherently social in nature. All novel tasks were developed and piloted with healthy undergraduates. A group of patients with moderate to severe TBI (N = 16), and a group of non-brain damaged controls (N = 16) underwent neuropsychological testing. Standard neuropsychological measures including the Wechsler Test of Adult Reading, Digit Span and Digit Symbol Coding from the Wechsler Adult Intelligence Scale, phonemic (FAS) and semantic fluency (Animals) from the Verbal Fluency Test, and the Trail Making Test, as well as the novel measures to both patients with TBI and controls were administered. The following predictions were made: vi 1) The novel performance-based measures of social abilities would be more sensitive to the presence of moderate and severe TBI than the standard neuropsychological measures of cognition; 2) On the informant version of the GIST, but not the self-report version, patients would have scores than controls; 3) Patients’ performance on the ASC would be less accurate than controls’, and this difference would be associated with real-world social skills, measured by the informant-version of the GIST; 4) Patients’ AIT performance would be less accurate than controls’, and this would be related to their self-rated emotional changes; 5) Patients’ SIT performance would be less accurate than controls’, and this difference would be associated with real-world social skills, again measured by the informant-version of the GIST. Findings: Findings were consistent with these hypotheses: 1) A statistically significant logistic regression revealed that a Social composite variable comprising the ASC, AIT and SIT was more sensitive to the presence of TBI (β = 9.59, p < .05) than a Cognitive composite variable comprising Digit Symbol Coding, Trails B completion time, and Phonemic Fluency (β = 0.006, p = .466). 2) A multivariate analysis of variance (MANOVA) revealed that informants of patients gave lower GIST scores to patients than the informants of controls (F(1,28) = 22.2, p < 0.0001), whereas there were no differences between groups on the self-rated version of the GIST (F(1,28) = .35, p = .56); 3) Patients’ ASC performance was significantly poorer than controls’ on a MANOVA (F(1,31) = 21.7, p < .0001), and ASC total scores were significantly correlated with GIST informant scores, using Spearman’s rank-order correlations (ρ(31) = .624, p < .0001). 4) Patients’ AIT performance was significantly poorer than controls’ using an independent samples t test (t(13) = 1.43, p < 0.005), and qualitative investigation of subjective reports of emotional change among patients suggested a potential relationship between emotional changes and AIT performance. vii 5) Patients’ SIT performance was significantly poorer than controls on an independent samples t test (t(30) = -2.12, p < 0.05), and SIT scores were significantly correlated with GIST informant scores, using Spearman’s rank-order correlations (ρ(31) = .460, p < .0001). Interpretation: This research represents a preliminary step in the development of clinically useful measures of social and emotional difficulties following TBI. Given the small sample size of the patient group, and the presence of co-morbid difficulties among some of the participants in this research, further testing of these measures in larger, more homogeneous samples would strengthen the current results, as would using a comparison group of people with milder TBI, rather than neuro-typical controls. The complexity of social behaviour requires that the current measures be further validated against other real-world assessments of social ability, and that assessments of other aspects of social behaviour be conducted. Nonetheless, the measures described here are a promising start to supplementing the neuropsychological toolkit in an area that requires further development at the present time.

The dementias are persistent or progressive disorders affecting more than one cognitive domain that interfere with an individual’s ability to function at work or home, and represent a decline from a previous level of function. In this thesis I consider the neurophysiology of dementia at a number of levels. I investigate the ways in which the connectivity and function of the brain predisposes to the specific focal patterns of neurodegeneration seen in the various dementias. I aim to identify the mesoscopic changes that occur in individuals with neurodegeneration and how these relate to their cognitive difficulties. I show how, by assessing patients in whom there is focal disruption of brain networks and observing the outcomes in comparison to controls, I can gain insight into the mechanisms by which the normal brain makes predictions and processes language. In Chapter 1, I set the scene for the focussed experimental investigations of model diseases by beginning with an introductory, clinically-focussed review that sets out the features, aetiology, management, epidemiology and prognosis of the dementias. This places these model diseases in the context of the broader clinical challenge posed by the dementias. In Chapter 2, I turn to ‘prototypical’ model diseases that represent neurodegenerative tauopathies with predominantly cortical (Alzheimer’s disease, AD) and subcortical (Progressive Supranuclear Palsy, PSP) disease burdens. I investigate the neurophysiological causes and consequences of Tau accumulation by combining graph theoretical analyses of resting state functional MR imaging and in vivo ‘Tau’ PET imaging using the ligand AV-1451. By relating Tau distribution to the functional connectome I provide in vivo evidence consistent with ‘prion-like’ trans-neuronal spread of Tau in AD but not PSP. This provides important validation of disease modification strategies that aim to halt or slow down the progression of AD by sequestration of pathological Tau in the synapse. In contrast, I demonstrate associations consistent with regional vulnerability to Tau accumulation due to metabolic demand and a lack of trophic support in PSP but not AD. With a cross-sectional approach, using Tau burden as a surrogate marker of disease severity, I then go on to show how the changes in functional connectivity that occur as disease progresses account for the contrasting cognitive phenotypes in AD and PSP. In advancing AD, functional connectivity across the whole brain becomes increasingly random and disorganised, accounting for symptomatology across multiple cognitive domains. In advancing PSP, by contrast, disrupted cortico-subcortical and cortico-brainstem interactions meant that information transfer passed through a larger number of cortical nodes, reducing closeness centrality and eigenvector centrality, while increasing weighted degree, clustering, betweenness centrality and local efficiency. Together, this resulted in increasingly modular processing with inter-network communication taking less direct paths, accounting for the bradyphrenia characteristic of the ‘subcortical dementias’. From chapter 3 onwards, I turn to the in-depth study of a model disease called non-fluent variant Primary Progressive Aphasia (nfvPPA). This disease has a clear clinical phenotype of speech apraxia and agrammatism, associated with a focal pattern of mild atrophy in frontal lobes. Importantly, general cognition is usually well preserved until late disease. In chapter 3 itself, I relate an experiment in which patients with nfvPPA and matched controls performed a receptive language task while having their brain activity recorded with magnetoencephalography. I manipulated expectations and sensory detail to explore the role of top-down frontal contributions to predictive processes in speech perception. I demonstrate that frontal neurodegeneration led to inflexible and excessively precise predictions, and that fronto-temporal interactions play a causal role in reconciling prior predictions with degraded sensory signals. The discussion here concentrates on the insights provided by neurodegenerative disease into the normal function of the brain in processing language. Overall, I demonstrate that higher level frontal mechanisms for cognitive and behavioural flexibility make a critical functional contribution to the hierarchical generative models underlying speech perception In chapter 4, I precisely define the sequence processing and statistical learning abilities of patients with nfvPPA in comparison to patients with non-fluent aphasia due to stroke and neurological controls. I do this by exposing participants to a novel, mixed-complexity artificial grammar designed to assess processing of increasingly complex sequencing relationships, and then assessing the degree of implicit rule learning. I demonstrate that agrammatic aphasics of two different aetiologies are not disproportionately impaired on complex sequencing relationships, and that the learning of phonological and non-linguistic sequences occurs independently in health and disease. In chapter 5, I summarise the synergies between the experimental chapters, and explain how I have applied a systems identification framework to a diverse set of experimental methods, with the common goal of defining the physiology of dementia. I then return to the results of chapter 3 with a clinical focus to explain how inflexible predictions can account for subjective speech comprehension difficulties, auditory processing abnormalities and (in synthesis with chapter 4) receptive agrammatism in nfvPPA. Overall, this body of work has contributed to knowledge in several ways. It has achieved its tripartite aims by: 1) Providing in vivo evidence consistent with theoretical models of trans-neuronal Tau spread (chapter 2), and a comprehensive clinical account of the previously poorly-understood receptive symptomatology of nfvPPA (chapter 5), thus demonstrating that systems neuroscience can provide a translational bridge between the molecular biology of dementia and clinical trials of therapies and medications. In this way, I begin to disentangle the network-level causes of neurodegeneration from its consequences. 2) Providing evidence for a causal role for fronto-temporal interactions in language processing (chapter 3), and demonstrating domain separation of statistical learning between linguistic and non-linguistic sequences (chapter 4), thus demonstrating that studies of patients with neurodegenerative disease can further our understanding of normative brain function. 3) Successfully integrating neuropsychology, behavioural psychophysics, functional MRI, structural MRI, magnetoencephalography and computational modelling to provide comprehensive research training, as the platform for a future research programme in the physiology of dementia.