Distinguishing the effect of lesion load from tract disconnection in the arcuate and uncinate fasciculi

Brain imaging studies of functional outcomes after white matter damage have quantified the severity of white matter damage in different ways. Here we compared how the outcome of such studies depends on two different types of measurements: the proportion of the target tract that has been destroyed (‘lesion load’) and tract disconnection. We demonstrate that conclusions from analyses based on two examples of these measures diverge and that conclusions based solely on lesion load may be misleading. First, we reproduce a recent lesion-load-only analysis which suggests that damage to the arcuate fasciculus, and not to the uncinate fasciculus, is significantly associated with deficits in fluency and naming skills. Next, we repeat the analysis after replacing the measures of lesion load with measures of tract disconnection for both tracts, and observe significant associations between both tracts and both language skills: i.e. the change increases the apparent relevance of the uncinate fasciculus to fluency and naming skills. Finally we show that, in this dataset, disconnection data explains significant variance in both language skills that is not accounted for by lesion load or volume, but lesion load data explains no unique variance in those skills, once disconnection and lesion volume are taken into account

White matter abnormalities in adults with bipolar disorder type-II and unipolar depression

Discerning distinct neurobiological characteristics of related mood disorders such as bipolar disorder type-II (BD-II) and unipolar depression (UD) is challenging due to overlapping symptoms and patterns of disruption in brain regions. More than 60% of individuals with UD experience subthreshold hypomanic symptoms such as elevated mood, irritability, and increased activity. Previous studies linked bipolar disorder to widespread white matter abnormalities. However, no published work has compared white matter microstructure in individuals with BD-II vs. UD vs. healthy controls (HC), or examined the relationship between spectrum (dimensional) measures of hypomania and white matter microstructure across those individuals. This study aimed to examine fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) across BD-II, UD, and HC groups in the white matter tracts identified by the XTRACT tool in FSL. Individuals with BD-II (n = 18), UD (n = 23), and HC (n = 24) underwent Diffusion Weighted Imaging. The categorical approach revealed decreased FA and increased RD in BD-II and UD vs. HC across multiple tracts. While BD-II had significantly lower FA and higher RD values than UD in the anterior part of the left arcuate fasciculus, UD had significantly lower FA and higher RD values than BD-II in the area of intersections between the right arcuate, inferior fronto-occipital and uncinate fasciculi and forceps minor. The dimensional approach revealed the depression-by-spectrum mania interaction effect on the FA, RD, and AD values in the area of intersection between the right posterior arcuate and middle longitudinal fasciculi. We propose that the white matter microstructure in these tracts reflects a unique pathophysiologic signature and compensatory mechanisms distinguishing BD-II from UD

A study of Clinico-Neuroradiologic Correlation in Patients with Dementia

INTRODUCTION: Dementia is characterized by decline in the cognitive functioning of an individual that significantly affects the quality of life and intrudes into the activity of daily living. The prevalence of dementia is increasing and is on the rise. This is due to the increased longevity that has resulted in increasing proportions of elderly population in whom the prevalence of dementia is higher. Dementia is defined by the DSM 5 criteria as decline from previously established baseline in the at least one of the cognitive domains: Memory and learning, executive function, language, complex attention, social cognition and perceptual motor function and it affects the activities of daily living. The symptoms in these patients do not occur exclusively during delirium and are not explainable by psychiatric disorder. AIM OF THE STUDY: To study the association between clinical deficits in cognitive domains of attention, memory and language in subjects with dementia and the neuroimaging correlates of the corresponding networks. OBJECTIVES: 1. To evaluate clinical deficits in cognitive domains of attention, memory and language in subjects with dementia. 2. To study the neuroimaging findings in subjects of Dementia on MR voxel based morphometry, MR diffusion tensor imaging and 18-Fluorodeoxyglucose Positron Emission Tomography in corresponding networks of attention, language and memory respectively. 3. To determine neuroimaging correlates of deficits in attention, language and memory in subjects with dementia in corresponding networks of attention, language and memory respectively. MATERIALS AND METHODS: Subjects attending dementia and cognitive neurosciences clinic at Rajiv Gandhi Government General Hospital, Chennai (RGGGH) were enrolled in the study. A total of 60 patients and 30 controls were recruited for the study. All the subjects were well informed about the study and the consent forms were obtained prior to the assessments. All the patients in the study underwent clinical examination for establishing the diagnosis of dementia. After the clinical assessment the subjects under investigation underwent four different types of assessments. The assessments include neuropsychological assessments, Voxel based Morphometry, Diffusion Tensor Imaging (for both controls and cases), and FDG-PET (for cases alone). METHODOLOGY: A random sample of 60 patients and 30 age-gender matched controls were selected from dementia and cognitive neurosciences clinic at Rajiv Gandhi Government General Hospital(RGGGH), Chennai during Dec. 2014 – Feb. 2018. The study was approved by Institutional Ethical Committee of Rajiv Gandhi Government General Hospital, Chennai. Neuropsychological tests were performed after obtaining consents from the subjects or caretakers. Patients were selected on the basis of MoCA scores where a case with a MoCA score of below 27 and satisfying the inclusion/exclusion criteria has been treated as a patient and included in the present study. The following clinical assessments were made on each patient: Addenbrooke‘s Cognitive Examination III (ACE III), Wechsler‘s Memory Scale (WMS), Trail Making Test A & B (TMT), Auditory Verbal Learning Test (AVLT) and scores were assessed accordingly. Neuropsychological aspects of both patients and controls were assessed by a single trained clinical psychologist. RESULTS: Before carrying out the major study, a pilot study was conducted taking a random sample of 10 patients and 10 controls. Reliability and validity of the protocols used for carrying out the major study were computed using appropriate statistical tools such as Cronbach‘s alpha for reliability and expert opinion on the validity of the protocols. Reliability analysis was carried out using split half method and the Cronbach alpha for part 1 of the protocol was obtained as 0.913 and for part 2 it was 0.993. The overall reliability of the protocol was 0.937 indicating high reliability of the test schedule used in the present study. CONCLUSIONS: Patients and controls were well differentiated in all the neuro-psychological parameters, MoCA, Addenbrook‘s Cognitive Score, WMS, AVLT, Digit Span, Story Recall, and Complex figure. Patients are found to have low scores in all these aspects compared to controls. Stepwise regression analysis indicates scores in only five parameters, namely attention, memory, AVLT, Digit span, and complex figure are enough to classify a person as having dementia or a normal person with a prediction accuracy of nearly 99 per cent. All these neuro psychological parameters are interrelated to one another. Inter correlations of neuro psychological parameters are very high among patients compared to controls in the present study. Analysis of Diffusion Tensor Imaging indicates that the white matter tract, Superior Longitudinal Fasciculus does not play any major role in attention and language domain. In contrast, Fornix has a major role to play in the memory domain. All the metrics of DTI show significant difference between patients and controls in the white matter tract Fornix on either side of the brain. As far as the DTI metrics are concerned, all the metrics have the same levels on both sides of brain of patients and controls. In most of the white matter tracts, the metrics, RD, MD, and AD are found to be high among patients compared to controls. FA is found to be low among patients in white matter tracts like IFO and Fornix. The analysis of diffusion metrics suggests the varying involvement of the white matter fasciculi of the respective domains. Analysis of FDG PET data indicates that about 70 per cent to 93 per cent of patients have hypometabolism in all the five cortical areas of attention domain- frontal association, posterior cingulate, parietal association, anterior cingulate, and caudate regions on either side of brain. Similarly 77 to 91 per cent of patients have hypometabolism in cortical areas of language domain, frontal association, temporal association and parietal association regions on either side of brain. About 85 to 89 per cent of patients have hypometabolism on either side of anterior cingulate regions. Voxel based Morphometry analysis clearly indicated that the patients and controls are significantly different in the following gray matter hubs of Attention Network : Dorsolateral Prefrontal Cortex, Frontal Eye Field, Occipital Eye Field, Cingulate Cortex and Superior Parietal Lobule. Similar scenario is seen in gray matter hubs of language Network: Broca's Area, Wernicke's Area, and Geschwind‘s Area (Inferior Parietal Lobule). In gray matter hubs of Memory Network: Uncus, Hippocampus, and Nucleus Accumbens areas, patients are found to be significantly different from the controls

Lesion Quantification Toolkit: A MATLAB software tool for estimating grey matter damage and white matter disconnections in patients with focal brain lesions

Lesion studies are an important tool for cognitive neuroscientists and neurologists. However, while brain lesion studies have traditionally aimed to localize neurological symptoms to specific anatomical loci, a growing body of evidence indicates that neurological diseases such as stroke are best conceptualized as brain network disorders. While researchers in the fields of neuroscience and neurology are therefore increasingly interested in quantifying the effects of focal brain lesions on the white matter connections that form the brain\u27s structural connectome, few dedicated tools exist to facilitate this endeavor. Here, we present the Lesion Quantification Toolkit, a publicly available MATLAB software package for quantifying the structural impacts of focal brain lesions. The Lesion Quantification Toolkit uses atlas-based approaches to estimate parcel-level grey matter lesion loads and multiple measures of white matter disconnection severity that include tract-level disconnection measures, voxel-wise disconnection maps, and parcel-wise disconnection matrices. The toolkit also estimates lesion-induced increases in the lengths of the shortest structural paths between parcel pairs, which provide information about changes in higher-order structural network topology. We describe in detail each of the different measures produced by the toolkit, discuss their applications and considerations relevant to their use, and perform example analyses using real behavioral data collected from sub-acute stroke patients. We show that analyses performed using the different measures produced by the toolkit produce results that are highly consistent with results that have been reported in the prior literature, and we demonstrate the consistency of results obtained from analyses conducted using the different disconnection measures produced by the toolkit. We anticipate that the Lesion Quantification Toolkit will empower researchers to address research questions that would be difficult or impossible to address using traditional lesion analyses alone, and ultimately, lead to advances in our understanding of how white matter disconnections contribute to the cognitive, behavioral, and physiological consequences of focal brain lesions

Neuroplasticity of language networks in aphasia: advances, updates, and future challenges

Researchers have sought to understand how language is processed in the brain, how brain damage affects language abilities, and what can be expected during the recovery period since the early 19th century. In this review, we first discuss mechanisms of damage and plasticity in the post-stroke brain, both in the acute and the chronic phase of recovery. We then review factors that are associated with recovery. First, we review organism intrinsic variables such as age, lesion volume and location and structural integrity that influence language recovery. Next, we review organism extrinsic factors such as treatment that influence language recovery. Here, we discuss recent advances in our understanding of language recovery and highlight recent work that emphasizes a network perspective of language recovery. Finally, we propose our interpretation of the principles of neuroplasticity, originally proposed by Kleim and Jones (1) in the context of extant literature in aphasia recovery and rehabilitation. Ultimately, we encourage researchers to propose sophisticated intervention studies that bring us closer to the goal of providing precision treatment for patients with aphasia and a better understanding of the neural mechanisms that underlie successful neuroplasticity.P50 DC012283 - NIDCD NIH HHSPublished versio

Examining Brain Connectivity and Reading Ability in Children

In this thesis, I investigated the relationship between functional and structural connectivity and reading ability in children. Prior research has tended to use single word reading measures or composite measures, however this is problematic as reading is a complex skill relying on multiple subskills, such as decoding efficiency, sight word reading efficiency, reading comprehension, and rapid automatized naming. As a result, the multi-faceted relationship between brain connectivity and reading ability is not well understood. I aimed to address this issue by considering multiple reading subskills while examining the neural substrates of reading. In Chapter 2, I examined how individual differences in decoding efficiency, sight word reading efficiency, reading comprehension, and rapid automatized naming relate to resting-state functional connectivity from regions of the brain’s reading network. I found that distinct functional networks in both hemispheres of the brain support different components of reading in children. In Chapter 3, I built on these findings to examine how individual differences in the same reading subskills are associated with structural connectivity in reading-related white matter tracts, as measured by diffusion tensor imaging. Similar to Chapter 2, the results of Chapter 3 suggested that different components of reading ability are supported by structural characteristics in distinct bilateral tracts of the brain. Importantly, many of the effects observed in Chapters 2 and 3 were found to be specific to reading subskills and were not associated with more general cognitive abilities. In Chapter 4, I examined how improvements in reading ability are related to changes in structural and functional connectivity, by measuring brain connectivity pre- and post-intervention in a group of children with reading disability. I also investigated whether individual differences in the amount of improvement in reading ability post-intervention was predicted by pre-intervention brain connectivity. I found that gains in reading ability were associated with changes in resting-state functional connectivity, particularly between reading-related regions and frontal regions as well as regions of the default mode network. Changes in white matter microstructure of the right arcuate fasciculus were strongly associated with gains in single word reading abilities. Additionally, results showed that distinct pre-intervention characteristics of resting-state functional connectivity and white matter integrity predicted the magnitude of subsequent gains in reading ability following the reading intervention. Chapter 5 summarizes the findings of this thesis in relation to the current literature and presents recommendations for future research on reading ability and brain connectivity

Interpreting and validating complexity and causality in lesion-symptom prognoses

This paper considers the steps needed to generate pragmatic and interpretable lesion-symptom mappings that can be used for clinically reliable prognoses. The novel contributions are 3-fold. We first define and inter-relate five neurobiological and five methodological constraints that need to be accounted for when interpreting lesion-symptom associations and generating synthetic lesion data. The first implication is that, because of these constraints, lesion-symptom mapping needs to focus on probabilistic relationships between Lesion and Symptom, with Lesion as a multivariate spatial pattern, Symptom as a time-dependent behavioural profile and evidence that Lesion raises the probability of Symptom. The second implication is that in order to assess the strength of probabilistic causality, we need to distinguish between causal lesion sites, incidental lesion sites, spared but dysfunctional sites and intact sites, all of which might affect the accuracy of the predictions and prognoses generated. We then formulate lesion-symptom mappings in logical notations, including combinatorial rules, that are then used to evaluate and better understand complex brain-behaviour relationships. The logical and theoretical framework presented applies to any type of neurological disorder but is primarily discussed in relationship to stroke damage. Accommodating the identified constraints, we discuss how the 1965 Bradford Hill criteria for inferring probabilistic causality, post hoc, from observed correlations in epidemiology - can be applied to lesion-symptom mapping in stroke survivors. Finally, we propose that rather than rely on post hoc evaluation of how well the causality criteria have been met, the neurobiological and methodological constraints should be addressed, a priori, by changing the experimental design of lesion-symptom mappings and setting up an open platform to share and validate the discovery of reliable and accurate lesion rules that are clinically useful