Neurological disorders require varying types and degrees of treatments depending on the symptoms and underlying causes of the disease. Patients suffering from medication-refractory symptoms often undergo further treatment in the form of brain stimulation, e.g. electroconvulsive therapy (ECT), transcranial direct current stimulation (tDCS), deep brain stimulation (DBS), or transcranial magnetic stimulation (TMS). These treatments are popular and have been shown to relieve various symptoms for patients with neurological conditions. However, the underlying effects of the stimulation, and subsequently the causes of symptom-relief, are not very well understood. In particular, TMS is a non-invasive brain stimulation therapy which uses time-varying magnetic fields to induce electric fields on the conductive parts of the brain. TMS has been FDA-approved for treatment of major depressive disorder for patients refractory to medication, as well as symptoms of migraine. Studies have shown that TMS has relieved severe depressive symptoms, although researchers believe that it is the deeper regions of the brain which are responsible for symptom relief. Many experts theorize that cortical stimulation such as TMS causes brain signals to propagate from the cortex to these deep brain regions, after which the synapses of the excited neurons are changed in such a way as to cause plasticity. It has also been widely observed that stimulation of the cortex causes signal firing at the deeper regions of the brain. However, the particular mechanisms behind TMS-caused signal propagation are unknown and understudied. Due to the non-invasive nature of TMS, this is an area in which investigation can be of significant benefit to the clinical community. We posit that a deeper understanding of this phenomenon may allow clinicians to explore the use of TMS for treatment of various other neurological symptoms and conditions. This thesis project seeks to investigate the various effects of TMS in the human brain, with respect to brain tissue stimulation as well as the cellular effects at the level of neurons. We present novel models of motor neuron circuitry and fiber tracts that will aid in the development of deep brain stimulation modalities using non-invasive treatment paradigms.

The human central nervous system (CNS) is capable of significant architectural and physiological reorganization in response to environmental stimuli. Novel sensorimotor experiences stimulate neuronal networks to modify their intrinsic excitability and spatial connectivity within and between CNS structures. Early learning-induced adaptations in the primary motor cortex are thought to serve as a priming stimulus for long term CNS reorganization underlying long-lasting changes in motor skill. Recent animal and human studies suggest that whole body exercise and core temperature elevation as systemic stressors also recruit activity-dependent processes that prime the motor cortex, cerebellum, and hippocampus to process sensorimotor stimuli from the environment, enhancing overall CNS learning and performance. A primary goal of rehabilitation specialists is to evaluate and design activity-based intervention strategies that induce or enhance beneficial neuroplastic processes across the lifespan. As such, an investgation of the influence of physical, non-pharmacological interventions on cortical excitability, motor learning, and cognitive function provide the central theme of this dissertation. The first study investigated the effects of a visually-guided motor learning task on motor cortex excitability at rest and during voluntary activation measured via transcranical magnetic stimulation (TMS). Motor learning significantly increased resting cortical excitability that was not accompanied by changes in excitability as a function of voluntary muscle activation. The cortical silent period, a measure of inhibition, increased after learning and was associated with the magnitude of learning at low activation. These findings suggest that separate excitatory and inhibitory mechanisms may influence motor output as a function of learning success. The following studies investigated the influence of systemic whole-body thermal stress on motor cortex excitability, motor learning and cognitive performance. We established the reliability of a novel TMS cortical mapping procedure to study neurophysiological responses after whole-body heat stress. Heat stress significantly potentiated motor cortex excitability, though acute motor learning and cognitive test performance did not differ between subjects receiving heat stress and control subjects. Future research is needed to delineate the potential of whole body heat stress as a therapeutic modality to influence central nervous system plasticity and performance.

This thesis describes a series of experiments to investigate the effect of thermal stimulation on corticospinal excitability using transcranial magnetic stimulation (TMS). Experiment I showed that innocuous cooling or warming of a single digit, produced short-lasting and mixed patterns of modulation only during actual thermal stimulation, with the inhibition being the most common pattern observed. In line with this finding, cooling stimulation applied to a larger area (i.e. multi-digits) produced variable but more sustained modulation in motor evoked potential (MEP) amplitude in the post-cooling phase (Exp II). Notably, the responses to cooling in terms of either suppressed or enhanced corticospinal excitability tended to be fairly consistent in a given individual with repeated applications. When examining possible sources of the observed variable MEP modulation, we found that individual characteristics such as age, sex and changes in skin temperature had no major influences. We hypothesized that the variability of responses might be related to individual differences in the excitability of intra-cortical circuits involved in sensorimotor integration. To test this hypothesis, we performed Experiment III using conditioning TMS paradigms. This experiment revealed that TMS markers of sensorimotor integration (SAI and SAF levels) were good predictors of individual variations in cooling-induced modulation in corticospinal excitability. This provided evidence supporting the role of SAI and SAF as markers to predict individual’s response to focal thermal stimulation. The identification of such predictors could enhance the therapeutic applicability of this form of stimulation in neurorehabilitation. Collectively, these findings advance our understanding of the neurophysiological basis of thermal stimulation and shed light on the development of a more rational application of neurofacilitation techniques based on afferent stimulation in clinical populations, such as stroke survivors.

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An important aspect of cognitive neuroscience is to localise specific brain regions involved in cognitive tasks, and to determine the mediating brain processes. There are several investigative approaches towards this, but amongst them, only transcranial magnetic stimulation (TMS) is able to interfere with the brain in such a way as to show the critical involvement of a brain region in a particular behaviour. TMS can be applied in normal subjects during the performance of a cognitive task and the resulting disruption of activity in the targeted brain region leads to an alteration in, or suspension of, behaviour consequent upon that brain activity. More recently, another brain stimulation technique has emerged that may also be able to contribute to the investigation of human cognition. Transcranial direct current stimulation (tDCS) applies a weak direct current to a targeted brain region, modulating cortical excitability and thereby altering the behavioural output. tDCS may be able to provide information that complements TMS and other investigative techniques by modulating behaviour in a way that depends on the role the brain region is carrying out in the task. This thesis describes a series of experiments in which TMS and tDCS were applied to two well-studied cognitive behaviours, working memory (WM) and mental rotation (MR). WM is the temporary retention of information that can be manipulated in order to guide behaviour. The most popular psychological model of WM proposes a multi-modal central executive (CE) that acts upon information stored in dedicated buffers (Baddeley, 1986). The dorsolateral prefrontal cortex (DLPFC) is a strong candidate as a key CE node (D'Esposito & Postle, 2000; Petrides, 2000b; Smith & Jonides, 1997; Stuss & Knight, 2002). MR is a visuo-cognitive process by which an image can be mentally modified into an orientation other than the one in which it is displayed (Corballis & McLaren, 1984). The area centred around the intraparietal sulcus is a brain key region for MR (Alivisatos & Petrides, 1996; Harris et al., 2000; Jordan et al., 2001). The work presented in this thesis examines the roles of the DLPFC and posterior parietal cortex (PPC) in WM and MR, respectively, and also highlights some of the methodological issues that are necessary to consider in order to produce reliable virtual lesions. The studies were carried out in young healthy volunteers, and were approved by the institutional ethics committee. In one study, repetitive TMS (rTMS) was shown to disrupt the manipulation of verbal information held in WM when administered over the right DLPFC, a result which supports a process-based segregation of the human prefrontal cortex for WM. Low- and high-frequency rTMS did not disrupt performance on another popular test of executive processing, n-back, a result which suggests that specific stimulation and task conditions must be met in order to produce virtual lesions, but also questions the critical importance of recruitment of the DLPFC for a running span task. rTMS applied to the right PPC replicated results from a previous TMS investigation, supporting the critical role this region in the rotation of images (Harris & Miniussi, 2003). When the left PPC was stimulated, impairment was produced only for the rotation of inverted stimuli. A role for the left PPC in the rotation of objects-as-a-whole is proposed based on these findings. The use of tDCS in the investigation of WM and MR is amongst the first to be described. Stimulation of the left DLPFC led to decreased performance accuracy on a verbal WM task in a polarity-specific manner. The pattern of results produced supports the role of the DLPFC as a node of a CE. tDCS over the left DLPFC did not modulate n-back task performance, a result which supports the TMS results that the involvement of the left DLPFC is not critical to the successful performance of the n-back task, although methodological issues remain of concern in relation to this conclusion. MR was not affected by tDCS applied to the right PPC and this result is most likely a direct demonstration of the importance of electrode montage. In conclusion, these studies show that rTMS and tDCS can be usefully applied to create virtual cortical lesions or modulate cortical excitability during the performance of cognitive tasks in humans, and can play an important role in investigating cognitive neuropsychological models. More widespread use of these techniques to complement lesion studies and functional neuroimaging is recommended.

<p>Neuroimaging and neurophysiology techniques were used to study some aspects of cortical sensory and motor system reorganisation in patients in the chronic phase after stroke. Using Diffusion Tensor Imaging, we found that the degree of white matter integrity of the corticofugal tracts (CFT) was positively related to grip strength. Structural changes of the CFT were also associated with functional changes in the corticospinal pathways, measured using Transcranial Magnetic Stimulation. This suggests that structural and functional integrity of the CFT is essential for upper limb function after stroke.</p><p>Using functional magnetic resonance imaging (fMRI), to measure brain activity during slow and fast passive hand movements, we found that velocity-dependent brain activity correlated positively with neural contribution to passive movement resistance in the hand in ipsilateral primary sensory (S1) and motor (M1) cortex in both patients and controls. This suggests a cortical involvement in the hyperactive reflex response of flexor muscles upon fast passive stretch.</p><p>Effects of a four week passive-active movement training programme were evaluated in chronic stroke patients. The group improved in range of motion and upper limb function after the training. The patients also reported improvements in a variety of daily tasks requiring the use of the affected upper limb. </p><p>Finally, we used fMRI to explore if brain activity during passive hand movement is related to time after stroke, and if such activity can be affected with intense training. In patients, reduced activity over time was found in supplementary motor area (SMA), contralateral M1 and prefrontal and parietal association areas along with ipsilateral cerebellum. After training, brain activity increased in SMA, ipsilateral S1 and intraparietal sulcus, and contralateral cerebellum in parallel with functional improvements of the upper limb. The findings suggest a use-dependent modification of cortical activation patterns in the affected hand after stroke. </p>

A key issue in understanding how the brain functions is the ability to correlate functional information with anatomical localisation. Functional information can be provided by a variety of techniques like positron emission tomography (PET), functional MRI (fMRI), electroencephalography (EEG), magnetoencephalography (MEG) or transcranial magnetic stimulation (TMS). All these methods provide different, but complementary, information about the functional areas of the brain. PET and fMRI provide spatially accurate picture of brain regions involved in a given task. TMS permits to infer the contribution of the stimulated brain area to the task under investigation. EEG and MEG, which reflects brain activity directly, have temporal accuracy of the order of a millisecond. TMS, EEG and MEG are offset by their low spatial resolution. In this thesis, we propose two methods to improve the spatial accuracy of method based on TMS and EEG. The first part of this thesis presents an automatic method to improve the localisation of TMS points. The method enables real-time visualisation and registration of TMS evoked responses and MRI. A MF digitiser is used to sample approximately 200 points on the subject's head following a specific digitisation pattern. Registration is obtained by minimising the RMS point to surface distance, computed efficiently using the Euclidean distance transform. Functional maps are created from TMS evoked responses projected onto the brain surface previously segmented from MRI. The second part presents the possibilities to set up a brain-computer interface (BCI) based on reconstructed sources of EEG activity and the parameters to adjust. Reconstructed sources could improve the EEG spatial accuracy as well as add biophysical information on the origin of the signal. Both informations could improve the BCI classification step. Eight BCIs are built to enable comparison between electrode-based and reconstructed source-based BCIs. Tests on detection of laterality of upcoming hand movement demonstrate the interest of reconstructed sources.

Neuroimaging and neurophysiology techniques were used to study some aspects of cortical sensory and motor system reorganisation in patients in the chronic phase after stroke. Using Diffusion Tensor Imaging, we found that the degree of white matter integrity of the corticofugal tracts (CFT) was positively related to grip strength. Structural changes of the CFT were also associated with functional changes in the corticospinal pathways, measured using Transcranial Magnetic Stimulation. This suggests that structural and functional integrity of the CFT is essential for upper limb function after stroke. Using functional magnetic resonance imaging (fMRI), to measure brain activity during slow and fast passive hand movements, we found that velocity-dependent brain activity correlated positively with neural contribution to passive movement resistance in the hand in ipsilateral primary sensory (S1) and motor (M1) cortex in both patients and controls. This suggests a cortical involvement in the hyperactive reflex response of flexor muscles upon fast passive stretch. Effects of a four week passive-active movement training programme were evaluated in chronic stroke patients. The group improved in range of motion and upper limb function after the training. The patients also reported improvements in a variety of daily tasks requiring the use of the affected upper limb. Finally, we used fMRI to explore if brain activity during passive hand movement is related to time after stroke, and if such activity can be affected with intense training. In patients, reduced activity over time was found in supplementary motor area (SMA), contralateral M1 and prefrontal and parietal association areas along with ipsilateral cerebellum. After training, brain activity increased in SMA, ipsilateral S1 and intraparietal sulcus, and contralateral cerebellum in parallel with functional improvements of the upper limb. The findings suggest a use-dependent modification of cortical activation patterns in the affected hand after stroke.

Four experiments, using both humans and monkeys as participants, were conducted to investigate the similarities and differences in human and nonhuman primate numerical cognition. In Experiment 1 it was determined that both humans and monkeys display a SNARC effect, with similar symbolic distance effects for both species. In addition, both species were found to respond faster to congruent stimulus pairs. In Experiment 2 both species were found accurately to recognize quantitative stimuli when presented for durations of 150 msec in a divided visual field paradigm. Performance for humans and monkeys for numerals and dot-patterns was almost identical in terms of accuracy and response times. In Experiment 3 participants were required to make relative numerousness judgments in a divided visual field paradigm. Both species responded faster and more accurately to stimuli presented to the right visual field. Species differences appeared, with monkeys performing equally well on both trial types whereas the humans performed better on numeral trials than on dot trials. In Experiment 4 repetitive transcranial magnetic stimulation (rTMS) was combined with the divided visual field paradigm. Accuracy was significantly disrupted for both species when compared to a no stimulation condition. A facilitation effect was also evident with both species exhibiting significant decreases in response time for all trials. Right-handed participants took longer to respond to stimuli presented to the left visual field. These findings add to the body of knowledge regarding both the similarities and differences of how quantitative stimuli are processed by humans and monkeys.

Stamning är en komplex motorisk talstörning, vars neurologisk bakgrund fortfarande inte är klarlagd. En växande mängd studier ger dock stöd för att stamning kan vara orsakat av strukturella avvikelser i den vänstra hemisfären. En studie (Sommer et al., 2003) som använde transkraniell magnetstimulering (TMS) för att undersöka kortikal inhibition hos personer som stammar (PsS) fann som ett bi-fynd att den stammande gruppen hade signifikant högre motortrösklar (MT) för vänster hemisfärs handmotorarea, det vill säga att det krävdes starkare stimulering för att väcka en muskelrespons i den kontralaterala handen. Resultat har dock inte uppmärksammats av senare forskning, och behöver verifieras. Den aktuella studien syftade till att undersöka om PsS tenderar att ha förhöjda MT, samt om det finns avvikande hemisfärsskilnader i MT hos PsS. MT mättes från båda hemisfärernas handmotorareor hos 15 PsS och 15 matchade kontollförsökspersoner med flytande tal. Resultatet visade på signifikant avvikande lateralisering av MT (p = 0,005) hos PsS; tvärtemot gruppen med flytande tal visade den stammande gruppen tendens till lägst MT i höger hemisfär, med 6 av 15 stammande som hade starkare högersidig lateralisering än någon i kontrollgruppen. Samstämmigt med resultaten från Sommer et al. (2003) var MT för vänster hemisfär signifikant högre i den stammande gruppen jämfört med kontrollgruppen (p = 0,049). Däremot fanns ingen tendens till avvikande MT i höger hemisfär (p = 0,92). Den förhöjda vänstersidiga MT kan vara relaterad till strukturella avvikelser i vänster hemisfär hos PsS.