• Brain Development in the Fmr1 KO Mouse Model of Fragile X Syndrome

      Shi, Da; Gullapalli, Rao P.; McKenna, Mary C. (2017)
      Fragile X syndrome (FXS) is the most commonly inherited form of intellectual disability resulting from silencing of FMR1 gene and consequential absence of fragile X mental retardation protein. FXS is commonly studied in Fmr1 KO mouse, which displays similar behavioral and neurological deficits as FXS patients. Many studies have investigated immature Fmr1 KO brain, but little is known about alterations in brain maturation processes, including developmental changes in metabolites, white and gray matter morphology and brain network function. Alterations in metabolites from 1H-magnetic resonance spectroscopy between Fmr1 KO and WT mice revealed included myo-inositol at postnatal-day 30 (PND 30), and taurine at PND 18, 21, and 30. Next, developmental alterations in myelin and white matter were examined in fixed Fmr1 KO mouse brains compared to WT at PND 18, 21, 30 and 60 with histological staining of myelin and MRI techniques to measure volume and magnetization transfer ratio, which is sensitive to myelin proteins and lipids. Fmr1 KO mice revealed decreased myelin density and MTR at PND 18, increased at PND 30 and decreased at PND 60, suggesting altered pattern of myelin formation in Fmr1 KO mouse. Diffusion tensor imaging was used to study microstructural properties of white matter to provide insight into myelin and axon properties in fixed Fmr1 KO brains at PND 18, 21, 30 and 60. Decreased mean, axial and radial diffusivity was found at PND 21 and 30 in Fmr1 KO brains, suggesting alterations in myelin compaction and axonal organization. Finally, alterations in functional connectivity in Fmr1 KO mouse were studied using resting-state functional-MRI. The longitudinal results showed decreased functional connectivity in the auditory and somatomotor networks in Fmr1 KO brain compared to WT at PND 30 and not different by PND 60, suggesting a delay in development of the resting state networks in Fmr1 KO mice. The work in this thesis characterized metabolic, structural, and functional alterations in developing Fmr1 KO mouse brain.
    • An Investigation of the Default Mode Interference Hypothesis in Mild Traumatic Brain Injury

      Sours, Chandler; Gullapalli, Rao P. (2014)
      Traumatic brain injury (TBI) is a leading cause of death and lifelong disability throughout developed nations, resulting in an emotional burden on the patients and a vast financial burden on the nation. While the majority of these cases are mild in nature, current clinical imaging often fails to perceive the extent of this subtle injury, making it difficult to predict which of these individuals will go on to suffer from persistent post concussive symptoms. Through the use of resting state functional MRI (fMRI), resting state cerebral perfusion, and task based fMRI, we test the hypothesis that the diffuse neuronal damage associated with mild TBI (mTBI) interrupts large-scale network function resulting in cognitive and neuropsychological symptoms. The Default Mode Interference Hypothesis suggests that the interactions within and between the Default Mode Network (DMN), Task Positive Network (TPN), and Salience Network (SN) are associated with cognitive performance. Therefore, we focused our investigation upon these three networks. Using resting state fMRI on prospectively collected data, our results demonstrate reduced resting state functional connectivity (rs-FC) within the DMN and TPN, but increased rs-FC between the three networks across the acute, sub-acute, and chronic stages of injury. Furthermore, the alterations noted in rs-FC are exacerbated in mTBI patients with persistent symptoms and are associated with reduced cognitive performance. Through the use of resting state cerebral perfusion, our findings demonstrate an altered balance in network perfusion of the DMN and TPN that is more prominent in mTBI patients with greater symptom severity. Finally, through the use of task based fMRI during the N-back working memory paradigm, we note that mTBI patients reveal reduced deactivation of regions of the DMN, over recruitment of regions of the TPN, as well as regions of novel recruitment. Further, mTBI patients demonstrate reduced segregation between the DMN and TPN during the most cognitively demanding task. These findings provide strong evidence for the Default Mode Interference Hypothesis in mTBI. Through lending support that altered communication within these large-scale neural networks contributes to the persistence of post concussive symptoms, we provide a potential avenue for therapeutic intervention to mitigate post concussive symptoms.
    • Non-invasive Motor Cortex Neuromodulation Reduces Secondary Hyperalgesia and Enhances Activation of the Descending Pain Inhibitory System

      Meeker, Timothy Joseph; Greenspan, Joel D. (2017)
      Studies have demonstrated analgesic effects of motor cortex (M1) stimulation for several chronic pain disorders such as neuropathic pain and syndromes involving central sensitization. Central sensitization is an important factor in neuropathic pain, clinically manifested as hyperalgesia and allodynia beyond any apparent injury. We predicted M1 transcranial direct current stimulation (tDCS) would mitigate secondary hyperalgesia, with little or no effect on primary hyperalgesia. We used a capsaicin-heat pain (C-HP) model to elicit heat allodynia and secondary mechanical hyperalgesia in pain-free subjects. In an assessor and subject blind randomized sham-controlled trial, we found anodal M tDCS decreased the intensity and area of pinprick hyperalgesia more than cathodal or sham tDCS with a small to moderate effect size. In contrast, we found no difference among treatments on pain ratings during heat allodynia. These findings confirmed our predictions and support the hypothesis that M1-targeted neuromodulation diminishes central sensitization. To elucidate the mechanism driving analgesia, we repeated application of the C-HP model during anodal, cathodal or sham tDCS in an assessor-blind randomized controlled trial while capturing neurophysiological correlates using functional magnetic resonance imaging (fMRI). We hypothesized M1 anodal tDCS would enhance engagement of a descending pain modulatory (DPM) network in response to mechanical pain compared to cathodal or sham tDCS. Anodal tDCS normalized effects of central sensitization on mechanical pain responses in the DPM network. Anodal tDCS disrupted the normal covariation of mechanical pain processing with subjective pain intensity and blunted the effect of sensitization in primary somatosensory cortex. There were treatment associated differences in functional connectivity (FC) within the DPM network. We found M1 to PAG FC was significantly greater during pain after anodal versus cathodal tDCS. Differences in FC between pain and control states for anodal tDCS included disrupted FC between PAG and sensory regions in the parietal lobe as well as the rostral ventral medulla. No disruptions in FC between control and pain state were found after cathodal or sham stimulation. These results support the hypothesis that analgesia via M1 neuromodulation occurs through modulation of activity in the DPM network even at the earliest stages of therapy.