Structural alterations in cortical and thalamocortical white matter tracts after recovery from prefrontal cortex lesions in macaques

Unilateral damage to the frontoparietal network typically impairs saccade target selection within the contralesional visual hemifield. Severity of deficits and the degree of recovery have been associated with widespread network dysfunction, yet it is not clear how these behavioural and functional brain changes relate with the underlying structural white matter tracts. Here, we investigated whether recovery after unilateral prefrontal cortex (PFC) lesions was associated with changes in white matter microstructure across large-scale frontoparietal cortical and thalamocortical networks. Diffusion-weighted imaging was acquired in four male rhesus macaques at pre-lesion, week 1, and week 8-16 post-lesion when target selection deficits largely recovered. Probabilistic tractography was used to reconstruct cortical frontoparietal fiber tracts, including the superior longitudinal fasciculus (SLF) and transcallosal fibers connecting the PFC or posterior parietal cortex (PPC), as well as thalamocortical fiber tracts connecting the PFC and PPC to thalamic nuclei. We found that the two animals with small PFC lesions showed increased fractional anisotropy in both cortical and thalamocortical fiber tracts when behaviour had recovered. However, we found that fractional anisotropy decreased in cortical frontoparietal tracts after larger PFC lesions yet increased in some thalamocortical tracts at the time of behavioural recovery. These findings indicate that behavioural recovery after small PFC lesions may be supported by both cortical and subcortical areas, whereas larger PFC lesions may have induced widespread structural damage and hindered compensatory remodeling in the cortical frontoparietal network

Differential Contributions of Transcallosal Sensorimotor Fiber Tract Structure and Neurophysiologic Function to Manual Motor Control in Young and Older Adults.

Consider tying your shoes, one of the most automatic movements an adult performs. Each hand works independently during this task to accomplish a unified goal. With advanced age comes a decline in motor control affecting the ability of older adults to perform such activities of daily living. Specifically, older adults show pronounced deficits in the ability to perform tasks with both hands. I investigated whether age-related declines in callosal microstructural integrity and inhibitory function contribute to age differences in the ability to perform such tasks. In the first study I determined the relationship between corpus callosum microstructural integrity and interhemispheric inhibition in young adults. I found a positive relationship between interhemispheric inhibition and microstructure of interhemispheric fibers that was specific to tracts connecting the primary motor cortices. My second study revealed that young adults with greater interhemispheric inhibition had reduced motor overflow during a unimanual force production task; however these same individuals had the poorest performance during a bimanual independent force production task. I suggest that a high capacity for interhemispheric inhibition from one motor cortex to another can effectively prevent motor overflow during unimanual tasks, however it also limits the ability for optimal control during independent bimanual tasks, possibly due to a reduced capability for interhemispheric cooperation. My third study determined whether age reductions in callosal structure and inhibitory function underlie impairments in independent bimanual control. I found that better microstructure of callosal tracts connecting the two primary motor cortices was positively related to bimanual task performance in older adults, but negatively related to performance in young adults. Further, increased interhemispheric inhibition was related to poorer bimanual task performance in older adults across all tasks, whereas this relationship was only observed in young adults for the independent bimanual task. Collectively, the results of my dissertation have identified age reductions in callosal structure and their resultant impact on neurophysiological function and manual motor control. These studies provide a mechanistic understanding that can be leveraged for the design of targeted training interventions that will allow individuals with dysfunction of interhemispheric inhibition, to maintain independence and improve their quality of life.Ph.D.KinesiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/89624/1/bfling_1.pd

Associations between corpus callosum size and ADHD symptoms in older adults: The PATH through life study

Neuroimaging studies of attention-deficit/hyperactivity disorder (ADHD) have revealed deviations of the corpus callosum in children and adolescents. However, little is known about the link between callosal morphology and symptoms of inattention or hyperactivity in adulthood, especially later in life. Here, we investigated in a large population-based sample of 280 adults (150 males, 130 females) in their late sixties and early seventies whether ADHD symptoms correlate with callosal thickness. In addition, we tested for significant sex interactions, which were followed by correlation analyses stratified by sex. Within males, there were significant negative correlations with respect to inattention and hyperactivity in various callosal regions, including the anterior third, anterior and posterior midbody, isthmus, and splenium. A thinner corpus callosum may be associated with fewer fibers or less myelination of fibers. Thus, the observed negative correlations suggest impaired inter-hemispheric communication channels necessary to sustain motor control and attention, which may contribute to symptoms of hyperactivity, impulsivity and/or inattention. Interestingly, within females, callosal thickness was positively related to hyperactivity in a small area within the rostral body, suggesting a sexually dimorphic neurobiology of ADHD symptoms. Altogether, the present results may reflect a lasting relationship between callosal morphology and ADHD symptoms throughout life.The study was supported by NHMRC Grants 973302, 179805, 157125, 1063907 and ARC Grant 130101705. Nicolas Cherbuin is funded by ARC research fellowship 12010022, Kaarin Anstey by NHMRC research fellowships 1002560, and Debjani Das by NHMRC research fellowship 410215. This research was partly undertaken on the National Computational Infrastructure (NCI) facility in Canberra, Australia, which is supported by the Australian Commonwealth Government

Physiological and behavioural consequences of network breakdown in brain injury

Traumatic brain injury (TBI) is a major public health problem with a huge unmet need for effective long-term care. Advances in MRI technology using diffusion tensor imaging (DTI) have demonstrated structural abnormalities in patients with TBI, often not seen on conventional brain imaging. The structural and neuropsychological consequences are described in existing research. The aim of this thesis is to identify whether there are physiological and behavioural consequences of TBI, which may be contributing to the observed problems in daily activities associated with this condition. This will help to understand the devastating functional impact following TBI, and its neurorehabilitation needs. This thesis initially develops a study protocol to investigate the physiology in TBI. Initial work explores physiology in thirty four healthy individuals using transcranial magnetic stimulation (TMS) to produce a study protocol that can be used in the patient group. This examined a selection of pathways, including the assessment of callosal physiology using a twin coil TMS method to assess for interhemispheric inhibition. This protocol was used to assess seventeen TBI patients, and compared to healthy controls, and demonstrated that callosal transfer is physiologically different between the two groups. The behavioural consequences of callosal transfer were then explored through the development of a bimanual tapping task in twenty nine healthy participants. The behavioural consequences were then assessed in the same group of TBI patients, and compared to the control group. The TBI patients had comparable mean performance. However, the variability in performance was the main difference between the two groups. The MRI DTI metrics were then investigated in the TBI and control groups. A relationship between the physiology, behaviour and microstructure was then explored. Through this series of investigations this thesis hopes to increase existing understanding of the consequences of brain injury

MRI neuroimaging: language recovery in adult aphasia due to stroke

Thesis (Ph.D.)--Boston UniversityThis research focuses on the contribution of magnetic resonance imaging (MRI) to understanding recovery and treatment of aphasia in adults who have suffered a stroke. There are three parts. Part 1 presents the feasibility of the application of an overt, picture-naming, functional MRI (fMRI) paradigm to examine neural activity in chronic, nonfluent aphasia (four mild-moderate and one severe nonfluent/global patient). The advantages and disadvantages of an overt, object picture-naming, fMRI block-design paradigm are discussed. An overt naming fMRI design has potential as a method to provide insight into recovery from adult aphasia including plasticity of the brain after left hemisphere stroke and response to treatment. Part 2 uses the overt naming fMRI paradigm to examine changes in neural activity (neural plasticity) after a two-week series of repetitive transcranial magnetic stimulation (rTMS) treatments to improve picture naming in chronic nonfluent aphasia. An overview of rTMS and rationale for use of rTMS as a clinical treatment for aphasia is provided. Patterns of fMRI activation are examined in two patients with chronic nonfluent aphasia following a two-week series of 1 Hz rTMS treatments to suppress the right pars triangularis portion of the right hemisphere, Broca's homologue. One patient responded well, and the other did not. Differences in fMRI activation in response to the rTMS treatment for the two patients may be due to differences in the patients' lesion sites and extent of damage within each lesion site. Part 3 examines the area of the corpus callosum (CC) in 21 chronic nonfluent aphasia patients and 13 ageequivalent controls using structural MRI. Understanding brain morphology and potential atrophy of the CC in chronic stroke patients may shed light on alterations in the interhemispheric dynamics after stroke, especially patterns of brain reorganization during post-stroke language recovery. A decrease in interhemispheric connections has implications for mechanisms of language recovery and potential success with specific treatment methods. Future directions of both structural and functional neuroimaging to study language recovery in adult aphasia are discussed

Brain Microstructure: Impact of the Permeability on Diffusion MRI

Diffusion Magnetic Resonance Imaging (dMRI) enables a non invasive in-vivo characterization of the brain tissue. The disentanglement of each microstructural property reflected on the total dMRI signal is one of the hottest topics in the field. The dMRI reconstruction techniques ground on assumptions on the signal model and consider the neurons axons as impermeable cylinders. Nevertheless, interactions with the environment is characteristic of the biological life and diffusional water exchange takes place through cell membranes. Myelin wraps axons with multiple layers constitute a barrier modulating exchange between the axon and the extracellular tissue. Due to the short transverse relaxation time (T2) of water trapped between sheets, myelin contribution to the diffusion signal is often neglected. This thesis aims to explore how the exchange influences the dMRI signal and how this can be informative on myelin structure. We also aimed to explore how recent dMRI signal reconstruction techniques could be applied in clinics proposing a strategy for investigating the potential as biomarkers of the derived tissue descriptors. The first goal of the thesis was addressed performing Monte Carlo simulations of a system with three compartments: intra-axonal, spiraling myelin and extra-axonal. The experiments showed that the exchange time between intra- and extra-axonal compartments was on the sub-second level (and thus possibly observable) for geometries with small axon diameter and low number of wraps such as in the infant brain and in demyelinating diseases. The second goal of the thesis was reached by assessing the indices derived from three dimensional simple harmonics oscillator-based reconstruction and estimation (3D-SHORE) in stroke disease. The tract-based analysis involving motor networks and the region-based analysis in grey matter (GM) were performed. 3D-SHORE indices proved to be sensitive to plasticity in both white matter (WM) and GM, highlighting their viability as biomarkers in ischemic stroke. The overall study could be considered the starting point for a future investigation of the interdependence of different phenomena like exchange and relaxation related to the established dMRI indices. This is valuable for the accurate dMRI data interpretation in heterogeneous tissues and different physiological conditions

Functional and Structural Brain Reorganization After Unilateral Prefrontal Cortex Lesions In Macaques

Visually exploring the surrounding environment relies on attentional selection of behaviourally relevant stimuli for further processing. The prefrontal cortex contributes to target selection as part of a frontoparietal network that controls shifts of gaze and attention towards relevant stimuli. Evidence from stroke patients and nonhuman primate lesion studies have shown that unilateral damage to the prefrontal cortex commonly impairs the ability to allocate attention toward stimuli in the contralesional visual hemifield. Although these impairments often exhibit a gradual improvement over time, the neural plasticity that underlies recovery of function remains poorly understood. The main objective of this dissertation was to study the relationship between large-scale network reorganization and the recovery of lateralized target selection deficits. To that aim, endothelin-1 was used to produce unilateral ischemic lesions in the caudal lateral prefrontal cortex of four rhesus macaques. Longitudinal behavioural and neuroimaging data were collected before and after the lesions, including eye-tracking while monkeys performed free-choice and visually guided saccades, resting-state fMRI, and diffusion-weighted imaging. Chapter 2 investigated the effects of unilateral prefrontal cortex lesions on saccade target selection and oculomotor parameters to disentangle attentional and motor impairments in the lasting contralesional target selection deficit. Chapter 3 examined the resting-state functional reorganization in a frontoparietal network during recovery of contralesional target selection. Finally, Chapter 4 investigated microstructural changes in cortical white matter tracts from diffusion-weighted imaging after behavioural recovery compared to pre-lesion. In general, spatiotemporal patterns of functional and structural network reorganization differed based on the extent of prefrontal damage. Altogether, these studies characterized the recovery of lateralized target selection deficits in a macaque model of focal cerebral ischemia and demonstrated involvement of both contralesional and ipsilesional networks throughout behavioural recovery. The broad implication of this research is that a network perspective is fundamental to understanding compensatory mechanisms of brain reorganization underlying recovery of function

Telemetry Controlled Brain Machine Interface To Train Cortical Circuits

The goal of this dissertation is to document functional reorganization in rat primary somatosensory (SI) cortex. This work proposes to strengthen the interhemispheric connection between homotopic sites in forelimb barrel cortex (FBC) through intracortical microstimulation (ICMS) and induce functional reorganization whereby neurons in the FBC respond to new input from the ipsilateral forelimb. Furthermore, a wireless microstimulation and recording device was developed for producing enhancement and functional reorganization of cortical circuits in FBC. The goal of Experiment One was to test the hypothesis that layer V neurons projected to homotopic sites in contralateral layer V FBC. Retrograde or anterograde neuronal tracer injections were made to characterize the distribution of callosal projecting neurons in contralateral SI that terminate in layer VFBC and where layer V callosal projecting neurons terminate in contralateral SI. The results showed a differential pattern of interhemispheric connectivity between homotopic forelimb representations in layer V FBC. The goal of Experiment Two was to test the hypothesis that ICMS enhances the interhemispheric pathway and leads to functional reorganization. ICMS was delivered in vivo to the interhemispheric pathway between homotopic layer V barrel cortices and multiunit recordings were made to assess changes in firing rate. The results showed ICMS strengthens interhemispheric connectivity and leads to functional reorganization in rat FBC. The goal of Experiment Three was to develop an interactive telemetry-based neural interface device for the controlled delivery of ICMS and recording response activity in rodent. The device successfully delivered microstimulation to a single electrode in SIand recorded evoked responses from a separate electrode in contralateral SI. Its performance was shown to be comparable to commercial stimulating and recording systems. This system serves as a prototype of a wearable compact device. The data suggest that neurons in rat FBC can be induced to respond to new input from the ipsilateral forelimb by enhancing the interhemispheric pathway with ICMS. An interactive system for the controlled delivery of telemetry-based microstimulation and real-time recordings has been demonstrated in vivo. These studies provide the framework for subsequent studies of interhemispheric pathway enhancement and functional reorganization in freely moving rats