223 research outputs found

    Resting state fMRI study of brain activation using rTMS in rats

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    Background and purpose: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used to treat many neurological and psychiatric conditions. However, not much is known about the mechanisms underlying its efficacy because human rTMS studies are mostly non-invasive while most animal studies are invasive. Invasive animal studies allow for cellular and molecular changes to be detected and hence, have been able to show that rTMS may alter synaptic plasticity in the form of long-term potentiation. This is the first rodent study using non-invasive resting state functional magnetic resonance imaging (rs-fMRI) to examine the effects of low-intensity rTMS (LI-rTMS) in order to provide a more direct comparison to human studies. Methods: rs-fMRI data were acquired before and after 10 minutes of LI-rTMS intervention at one of four frequencies—1 Hz, 10 Hz, biomimetic high frequency stimulation (BHFS) and continuous theta burst stimulation (cTBS)—in addition to sham. We used independent component analysis to uncover changes in the default mode network (DMN) induced by each rTMS protocol. Results: There were considerable rTMS-related changes in the DMN. Specifically, (1) the synchrony of resting activity of the somatosensory cortex was decreased ipsilaterally following 10 Hz stimulation, increased ipsilaterally following cTBS, and decreased bilaterally following 1 Hz stimulation and BHFS; (2) the motor cortex showed bilateral changes following 1 Hz and 10 Hz stimulation, an ipsilateral increase in synchrony of resting activity following cTBS, and a contralateral decrease following BHFS; and (3) in the hippocampus, 10 Hz stimulation caused an ipsilateral decrease while 1 Hz and BHFS caused a bilateral decrease in synchrony. There was no change in the correlation of the hippocampus induced by cTBS. Conclusion: The present findings suggest that LI-rTMS can modulate functional links within the DMN of rats. LI-rTMS can induce changes in the cortex, as well as in remote brain regions such as the hippocampus when applied to anaesthetised rats and the pattern of these changes depends on the frequency used, with 10 Hz stimulation, BHFS and cTBS causing mostly ipsilateral changes in synchrony of activity in the DMN and 1 Hz stimulation causing bilateral changes in synchrony, with the contralateral changes being more prominent than ipsilateral changes. Hence, combined rTMS-fMRI emerges as a powerful tool to visualise rTMS-induced cortical connectivity changes at a high spatio-temporal resolution and help unravel the physiological processes underlying these changes in the cortex and interconnected brain regions

    Area 5 Influences Excitability within the Primary Motor Cortex in Humans

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    In non-human primates, Brodmann's area 5 (BA 5) has direct connectivity with primary motor cortex (M1), is largely dedicated to the representation of the hand and may have evolved with the ability to perform skilled hand movement. Less is known about human BA 5 and its interaction with M1 neural circuits related to hand control. The present study examines the influence of BA 5 on excitatory and inhibitory neural circuitry within M1 bilaterally before and after continuous (cTBS), intermittent (iTBS), and sham theta-burst stimulation (sham TBS) over left hemisphere BA 5. Using single and paired-pulse TMS, measurements of motor evoked potentials (MEPs), short interval intracortical inhibition (SICI), and intracortical facilitation (ICF) were quantified for the representation of the first dorsal interosseous muscle. Results indicate that cTBS over BA 5 influences M1 excitability such that MEP amplitudes are increased bilaterally for up to one hour. ITBS over BA 5 results in an increase in MEP amplitude contralateral to stimulation with a delayed onset that persists up to one hour. SICI and ICF were unaltered following TBS over BA 5. Similarly, F-wave amplitude and latency were unaltered following cTBS over BA 5. The data suggest that BA 5 alters M1 output directed to the hand by influencing corticospinal neurons and not interneurons that mediate SICI or ICF circuitry. Targeting BA 5 via cTBS and iTBS is a novel mechanism to powerfully modulate activity within M1 and may provide an avenue for investigating hand control in healthy populations and modifying impaired hand function in clinical populations

    Multimodal characterisation of sensorimotor oscillations

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    The studies in this project have investigated the ongoing neuronal network oscillatory activity found in the sensorimotor cortex using two modalities: magnetoencephalography (MEG) and in vitro slice recordings. The results have established that ongoing sensorimotor oscillations span the mu and beta frequency region both in vitro and in MEG recordings, with distinct frequency profiles for each recorded laminae in vitro, while MI and SI show less difference in humans. In addition, these studies show that connections between MI and SI modulate the ongoing neuronal network activity in these areas. The stimulation studies indicate that specific frequencies of stimulation affect the ongoing activity in the sensorimotor cortex. The continuous theta burst stimulation (cTBS) study demonstrates that cTBS predominantly enhances the power of the local ongoing activity. The stimulation studies in this project show limited comparison between modalities, which is informative of the role of connectivity in these effects. However, independently these studies provide novel information on the mechanisms on sensorimotor oscillatory interaction. The pharmacological studies reveal that GABAergic modulation with zolpidem changes the neuronal oscillatory network activity in both healthy and pathological MI. Zolpidem enhances the power of ongoing oscillatory activity in both sensorimotor laminae and in healthy subjects. In contrast, zolpidem attenuates the “abnormal” beta oscillatory activity in the affected hemisphere in Parkinsonian patients, while restoring the hemispheric beta power ratio and frequency variability and thereby improving motor symptomatology. Finally we show that independent signals from MI laminae can be integrated in silico to resemble the aggregate MEG MI oscillatory signals. This highlights the usefulness of combining these two methods when elucidating neuronal network oscillations in the sensorimotor cortex and any interventions

    Developing a Brain‐Based, Non‐Invasive Treatment for Pain

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    Chronic pain cost society more than $500 billion each year and contributes to the ongoing opioid overdose crisis. Substantial risks and low efficacy are associated with opiate usage for chronic pain. This dissertation seeks to fill the urgent need for a new pain treatment using a neural-circuit based approach in healthy controls and chronic pain patients. First, we performed a single-blind study examining the causal effects of transcranial magnetic stimulation (TMS), compared to a well-matched control condition. Using interleaved TMS/fMRI we explored brain activation in response to dorsolateral prefrontal cortex (DLPFC) stimulation in 20 healthy controls. This study tested the hypothesis that the TMS evoked responses would be in frontostriatal locations. Consistent with this hypothesis active TMS, compared to the control, led to significantly greater activity in the caudate, thalamus and anterior cingulate cortex (ACC). Building on these findings, we developed a single-blind, sham-controlled study examining two TMS strategies for analgesia in 45 healthy controls. We completed an fMRI thermal pain paradigm before and after modulatory repetitive TMS at either the DLPFC or the medial prefrontal cortex (MPFC). Despite a role in pain processing, the MPFC has not yet been explored as a target for analgesia. Only MPFC stimulation significantly improved behavioral pain measures. These effects were associated with increased motor and parietal cortex activity during the pain task. We then supplement these findings by testing the hypothesis that chronic pain patients who use opioids (n=14) would have elevated brain responses to thermal pain relative to healthy controls (n=14). Despite indistinguishable self-report measures, we found increased brain activity in the ACC and sensory areas in patients which were positively correlated with opioid dose. We conclude by evaluating the feasibility of these approaches in chronic pain patients, reporting preliminary findings from a pilot study examining the two treatment strategies tested previously in controls. Collectively, our findings support a circuits-first approach to pain treatment. Though MPFC stimulation was effective in reducing pain in healthy controls, further work is required to confirm these results in a chronic pain population, as chronic pain and opioid usage alter how the brain processes the pain experience

    Investigating cerebellar contributions to sensory processing

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    Over the last two decades, the long-standing view of the cerebellum as a motor structure has been challenged with evidence highlighting the presence of cerebellar activation during non-motor tasks and functional connectivity studies emphasizing the importance of cerebellar input to associative cortical regions. The cerebellum has been widely agreed to be involved in coordinated movement. To successfully perform a smooth movement, we need to be able to gather information that is pertinent to completing the goal at hand and ignore erroneous information, which could be thought of as attention. Many of these studies have localized the right lateral cerebellum as the node primarily responsible for coordination of more cognitively driven processes, due to connectivity with prefrontal and frontal regions. Although it is widely agreed that the cerebellum aids in coordination via state estimation mechanisms, how it exerts this influence over higher order processes is not well understood; this is in part due to the variability of results from lesion studies. The purpose of this thesis is to investigate the nature of the cerebellum’s influence on higher-order processes within a young, healthy population. The aim of the first study was to determine the cerebellum’s influence over sensory processing without the need for an explicit movement task. Following the transient disruption of cerebellar activity using continuous theta burst stimulation (cTBS), Study 1 identified that the cerebellum was involved in distinguishing differences between types of sensory stimuli as indexed by changes in cortical electrical activity measured through electroencephalography (EEG). Specifically, decreases in the mismatch negativity (MMN) in response to the presence of deviant stimuli following administration of cTBS was observed. The aim of Study 2 was to further probe this concept using a sensory conflict task, which incorporated two different modalities of stimuli. Following cTBS to the right lateral cerebellum, the increases in the tactile N70 and visual P2 cortical peaks in response to irrelevant and distractor stimuli may be an indication of participants becoming less likely to ignore distractor stimuli. This is further supported by the concomitant decreases seen in accuracy. The final study of this thesis sought to strengthen our understanding of the nature of the cerebellar influence over attentional processes by assessing laterality and changing the side of cerebellar stimulation to the left side. In this way, it can be validated that the alterations observed in the previous studies are due to the hypothesized influence of right-cerebellum to left-side frontal areas as opposed to overall cerebellar control of sensorimotor processing. A lack of change within both somatosensory and visual peaks, the N70 and P2 respectively, following stimulation of the left lateral cerebellum supports the specificity of the cerebellum’s influence. Together, these studies aid in our understanding of how the cerebellum exerts its influence on widespread, contralateral higher-order networks through the comparison of contextual sensory information. This work serves to broaden our understanding of how the cerebellum is involved in behaviours which encompass sensory processing, movement and cognition to execute purposeful behaviour

    Cortical Sensorimotor Mechanisms for Neural Control of Skilled Manipulation

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    abstract: The human hand is a complex biological system. Humans have evolved a unique ability to use the hand for a wide range of tasks, including activities of daily living such as successfully grasping and manipulating objects, i.e., lifting a cup of coffee without spilling. Despite the ubiquitous nature of hand use in everyday activities involving object manipulations, there is currently an incomplete understanding of the cortical sensorimotor mechanisms underlying this important behavior. One critical aspect of natural object grasping is the coordination of where the fingers make contact with an object and how much force is applied following contact. Such force-to-position modulation is critical for successful manipulation. However, the neural mechanisms underlying these motor processes remain less understood, as previous experiments have utilized protocols with fixed contact points which likely rely on different neural mechanisms from those involved in grasping at unconstrained contacts. To address this gap in the motor neuroscience field, transcranial magnetic stimulation (TMS) and electroencephalography (EEG) were used to investigate the role of primary motor cortex (M1), as well as other important cortical regions in the grasping network, during the planning and execution of object grasping and manipulation. The results of virtual lesions induced by TMS and EEG revealed grasp context-specific cortical mechanisms underlying digit force-to-position coordination, as well as the spatial and temporal dynamics of cortical activity during planning and execution. Together, the present findings provide the foundation for a novel framework accounting for how the central nervous system controls dexterous manipulation. This new knowledge can potentially benefit research in neuroprosthetics and improve the efficacy of neurorehabilitation techniques for patients affected by sensorimotor impairments.Dissertation/ThesisDoctoral Dissertation Neuroscience 201
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