Blindsight is a phenomenon in which patients suffering damage to the primary visual cortex (V1) perceive themselves as blind, but nonetheless seem to have some residual capacity to distinguish between visual stimuli better than chance. Blindsight can be divided into two subtypes: blindsight type I and blindsight type II. Blindsight type I is defined as visual capacity in the absence of acknowledged awareness. Patients with blindsight type II have visual capacity with some feeling or sensation in the blind field. Visual pathways bypassing V1 are assumed to be responsible for the residual capacity in blindsight. To investigate whether these pathways are present in healthy individuals we examined if it is possible to induce blindsight in healthy individuals by reviewing studies that have tried to induce blindsight with transcranial magnetic stimulation (TMS). We found that TMS might be able to induce blindsight type I of side detection. We also found that TMS might be able to induce blindsight type II of colour, orientation, and trustworthiness. Further, we found that both conscious and unconscious perception of shapes are dependent on processing in early visual cortex (EVC) in healthy individuals. We conclude that the full capacity seen in blindsight is most probable caused by neural reorganisation post trauma. The visual pathways bypassing V1 are, if present in healthy individuals, too weak to influence behaviour with the possible exception of side detection. Additionally, we conclude that the use of a binary awareness scale in blindsight studies fails to capture vaguely seen stimuli.

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No / Until recently, it was widely believed that object position and object motion were represented independently in the visual cortex. However, several studies have shown that adaptation to motion produces substantial shifts in the perceived position of subsequently viewed stationary objects [[13]]. Two stages of motion adaptation have been proposed: an initial stage at the level of V1 and a secondary stage thought to be located in V5/MT [[4]]. Indeed, selective adaptation can be demonstrated at each of these levels of motion analysis [[5, 6]]. What remains unknown is which of these cortical sites are involved in modulating the positional representation of subsequently viewed objects. To answer this question directly, we disrupted cortical activity by using transcranial magnetic stimulation (TMS) immediately after motion adaptation. When TMS was delivered to V5/MT after motion adaptation, the perceived offset of the test stimulus was greatly reduced. In marked contrast, TMS of V1 had no effect on the changes that normally occur in perceived position after motion adaptation. This result demonstrates that the anatomical locus at which motion and positional information interact is area V5/MT rather than V1/V2.

Yes / Human neuropsychological and neuroimaging studies have raised the possibility that different attributes of optic flow stimuli, namely radial direction and the position of the focus of expansion (FOE), are processed within separate cortical areas. In the human brain, visual areas V5/MT+ and V3A have been proposed as integral to the analysis of these different attributes of optic flow stimuli. In order to establish direct causal relationships between neural activity in V5/MT+ and V3A and the perception of radial motion direction and FOE position, we used Transcranial Magnetic Stimulation (TMS) to disrupt cortical activity in these areas whilst participants performed behavioural tasks dependent on these different aspects of optic flow stimuli. The cortical regions of interest were identified in seven human participants using standard fMRI retinotopic mapping techniques and functional localisers. TMS to area V3A was found to disrupt FOE positional judgements, but not radial direction discrimination, whilst the application of TMS to an anterior sub-division of hV5/MT+, MST/TO-2, produced the reverse effects, disrupting radial direction discrimination but eliciting no effect on the FOE positional judgement task. This double dissociation demonstrates that FOE position and radial direction of optic flow stimuli are signalled independently by neural activity in areas hV5/MT+ and V3A. / This work was funded by the BBSRC (grant B/N003012/1).

Spreading depression (SD) is a slow propagating wave of depolarization that can spread throughout the cortex in the event of brain injury or any general energy failure of the brain. Massive cellular depolarization causes enormous ionic and water shifts and silences synaptic transmission in the affected tissue. Large amounts of energy are required to restore ionic gradients and are not always met. When these energetic demands are not met, brain tissue damage can occur. The exact mechanism behind initiation and propagation of SD are unknown, but a general model is known. It may be possible to prevent or delay the onset of SD using non-invasive electromagnetic techniques. Transcranial magnetic stimulation (TMS), electrical stimulation (ES), and transcranial direct coupled stimulation (tDCS) could be used to decrease neuronal excitability in different ways. In theory, any technique that can reduce cortical excitability could suppress SD initiating or propagating.

Movement training modulates the excitability in several cortical and subcortical areas. Compared to training with a single arm, movement training with both arms yields a greater increase in motor related cortical regions. A short-term session of bimanual training (BMT) enhances cortical activity of motor preparation and execution areas in both hemispheres. The underlying neural mechanisms for this increased activation with BMT are unclear, but may involve interhemispheric connections between homologous primary motor cortex (M1) representations and input from motor preparatory areas (i.e. dorsal premotor cortex (PMd)). Also, it is unclear how selective up-regulation or down-regulation of specific motor-related areas may contribute to changes in M1 excitability when combined with BMT. The work in this thesis investigated modulation of M1 excitability in terms of in-phase versus anti-phase BMT (Study #1), potentially up-regulating the left dorsal premotor cortex (lPMd) via iTBS before BMT (Study #2), theoretically down-regulating contralateral (right) M1 homologous representation before BMT (Study #3), and finally the potential intracortical and interhemispheric cortical adaptations in M1 bilaterally due to the same interventions as Study #2 (Study #4). For Study #1, it was hypothesized that in-phase BMT would lead to an increased excitability in M1. For Studies #2-4, it was hypothesized that modulation of motor-related areas would cause an increase in the excitability of left M1, and this modulation would be greater when combined with BMT. Study #1 found that in-phase, and not anti-phase BMT, lead to increase M1 excitability. Study #2 found that iTBS to lPMd followed by BMT caused a unique increase in M1 excitability, in terms of increased spatial extent and global MEP amplitude. Study #3 found that the combination of cTBS to right M1 with BMT caused greater excitability enhancements than either intervention alone. Finally, Study #4 found distinct modulations of cortical excitability within and across M1 bilaterally due to BMT, iTBS to lPMd and the combination of these interventions that involved long-interval inhibitory circuitry asymmetrically. Overall, this current work found that the modulation of remote cortical areas to M1 (i.e. lPMd and contralateral M1) in combination with movement training led to unique, and at times greater, excitability enhancements of M1 which could be advantageous in enhancing short-term plasticity in damaged M1.

Introduction: Memory is a complex cognitive process formerly linked to mechanisms of brain plasticity that can be estimated in the left dorsolateral prefrontal cortex (DLPFC) using transcranial magnetic stimulation and electroencephalography (TMS-EEG). Also, cortical thickness in the DLPFC may be a potential proxy measure of brain plasticity as previous literature reports a link between better memory and thicker cortex. However, the link between brain plasticity and memory performance as well as DLPFC thickness remains to be clarified. Methods: Intermittent theta burst stimulation (iTBS) probed plasticity-like mechanisms in the left DLPFC in 17 cognitively healthy participants. TMS-EEG recordings were performed before and after sham and active iTBS to quantify plasticity via transcranial magnetic stimulation-evoked potentials (TEPs). Composite memory scores for each domain (verbal episodic, visual episodic and working memory) were obtained using the Cambridge Neuropsychological Test Automated Battery. Anatomical T1 images were acquired by magnetic resonance imaging and processed by open-source software (CIVET) and the Automated Anatomical Labeling atlas to extract cortical thickness of the DLPFC. All statistical analyses (linear mixed model, Tukey's post hoc test and Pearson's correlations) were completed in R Studio. Results: iTBS resulted in increased TEP amplitude P30 (F= 5.239, p = 0.029), as shown by a significant interaction between condition (iTBS, sham) and time (pre- and post-condition). Specifically, Tukey's post hoc test revealed that the P30 increase was near trending significant post-iTBS compared to pre-iTBS for the active condition (p = 0.166) but not for the sham condition (p = 0.294). A trending significant relationship was observed between the magnitude of P30 change post-iTBS and thicker left DLPFC (r = 0.488; p = 0.108). Lastly, no significant relationships between P30 change and memory performance were observed. Conclusion: These preliminary findings suggest there could be a relationship between increased capacity for brain plasticity and a thicker left DLPFC. To further investigate these relationships, we plan to recruit additional cognitively healthy participants. Our preliminary findings support the foundation for future clinical studies in which DLPFC thickness could be explored as a predictive factor for response to plasticity-targeting iTBS treatment.

While fatigue is a common daily phenomenon, the exact relationship between perception of effort and fatigue is still unknown. Existing tools for assessing perception of effort are effectively limited to whole body exercise, while current methods for assessing voluntary activation are painful and not feasible for clinical application. The main aims of this thesis were to evaluate existing methodologies for their appropriateness in assessing perception of effort and voluntary activation following isolated muscle function testing, and to examine the relationship between subjective perception of effort and objective changes in the healthy motor control system. The implementation of reliable and valid assessment tools in clinical practice may enable clarification of the pathogenesis of many neurological conditions that have chronic fatigue as a key feature. Four studies of within-subjects repeated measures design have been conducted. Sixtynine healthy volunteers were recruited among staff and students of Brunel University. Magnetic stimulation was tested as a valid alternative to electrical stimulation in the conventional single-pulse Twitch Interpolation Technique. The 0–10 Numeric Rating Scale (NRS) was also tested for its reliability and validity in assessing the perception of effort during isometric exercise of elbow flexors. The changes of perception of effort following a submaximal elbow flexion fatiguing task, as well as following transcranial direct current stimulation (tDCS) over the motor cortex were also tested. The main findings showed significant differences between peripheral and magnetic stimulation in conventional single-pulse Twitch Interpolation Technique. The 0–10 NRS demonstrated linear properties and reported excellent test-retest reliability and good concurrent criterion validity in recording perception of effort under repeated isometric contractions of elbow flexors. Ten minutes of a submaximal intermittent isometric fatiguing exercise produced a significant elevation in rating of perceived effort, which was associated with central and peripheral neurophysiological changes of the motor control system. In contrast, perception of effort did not change significantly following 10 minutes of tDCS. The major findings of this thesis suggest the 0–10 NRS is a valid and reliable scale for rating perception of effort in healthy individuals. Further testing of the scale on patients is needed to establish its validity in clinical settings. Additionally, the findings indicate a substantial role of perception of effort in the voluntary motor control system. However, further research towards revealing the underlying mechanisms of perceived effort regulation in both health and disease is required.

The present work introduces a synthesis of neocerebellar state estimation and feedforward control with multi-level language processing. The approach combines insights from clinical, imaging, and modelling work on the cerebellum with psycholinguistic and historical linguistic research. It finally provides the first experimental attempts towards the empirical validation of this synthesis, employing transcranial magnetic stimulation. A neuroanatomical locus traditionally seen as limited to lower sensorimotor functions, the cerebellum has, over the last decades, emerged as a widely accepted foundation of feedforward control and state estimation. Its cytoarchitectural homogeneity and diverse connectivity with virtually all parts of the central nervous system strongly support the idea of a uniform, domain-general cerebellar computation. Its reciprocal connectivity with language-related cortical areas suggests that this uniform cerebellar computation is also applied in language processing. Insight into the latter, however, remains an elusive desideratum; instead, research on cerebellar language functions is predominantly involved in the frontal cortical-like deficits (e.g. aphasias) seldom induced by cerebellar impairment. At the same time, reflections on cerebellar computations in language processing remain at most speculative, given the lack of discourse between cerebellar neuroscientists and psycholinguists. On the other hand, the fortunate contingency of the recent accommodation of these computations in psycholinguistic models provides the foundations for satisfying the desideratum above. The thesis thus formulates a neurolinguistic model whereby multi-level, predictive, associative linguistic operations are acquired and performed in neocerebello-cortical circuits, and are adaptively combined with cortico-cortical categorical processes. A broad range of psycholinguistic phenomena, involving, among others, "pragmatic normalization", "verbal/semantic illusions", associative priming, and phoneme restoration, are discussed in the light of recent findings on neocerebellar cognitive functions, and provide a rich research agenda for the experimental validation of the proposal. The hypothesis is then taken further, examining grammaticalization changes in the light of neocerebellar linguistic contributions. Despite a) the broad acceptance of routinization and automatization processes as the domain-general core of grammaticalization, b) the growing psycholinguistic research on routinized processing, and c) the evidence on neural circuits involved in automatization processes (crucially involving the cerebellum), interdisciplinary discourse remains strikingly poor. Based on the above, a synthesis is developed, whereby grammaticalization changes are introduced in routinized dialogical interaction as the result of maximized involvement of associative neocerebello-cortical processes. The thesis then turns to the first steps taken towards the verification of the hypothesis at hand. In view of the large methodological limitations of clinical research on cerebellar cognitive functions, the transcranial magnetic stimulation apparatus is employed instead, producing the very first linguistic experiments involving cerebellar stimulation. Despite the considerable technical difficulties met, neocerebellar loci are shown to be selectively involved in formal- and semantic-associative computations, with far-reaching consequences for neurolinguistic models of sentence processing. In particular, stimulation of the neocerebellar vermis is found to selectively enhance formal-associative priming in native speakers of English, and to disrupt, rather selectively, semantic-categorical priming in native speakers of Modern Greek, as well as to disrupt the practice-induced facilitation in processing repeatedly associated letter strings. Finally, stimulation of the right neocerebellar Crus I is found to enhance, quite selectively, semantic-associative priming in native speakers of English, while stimulation of the right neocerebellar vermis is shown to disrupt semantic priming altogether. The results are finally discussed in the light of a future research agenda overcoming the technical limitations met here.

<p>Making decisions is fundamental to everything we do, yet it can be impaired in various disorders and conditions. While research into the neural basis of decision-making has flourished in recent years, many questions remain about how decisions are instantiated in the brain. Here we explored how primates make abstract decisions and decisions in social contexts, as well as one way to non-invasively modulate the brain circuits underlying decision-making. We used rhesus macaques as our model organism. First we probed numerical decision-making, a form of abstract decision-making. We demonstrated that monkeys are able to compare discrete ratios, choosing an array with a greater ratio of positive to negative stimuli, even when this array does not have a greater absolute number of positive stimuli. Monkeys’ performance in this task adhered to Weber’s law, indicating that monkeys—like humans—treat proportions as analog magnitudes. Next we showed that monkeys’ ordinal decisions are influenced by spatial associations; when trained to select the fourth stimulus from the bottom in a vertical array, they subsequently selected the fourth stimulus from the left—and not from the right—in a horizontal array. In other words, they begin enumerating from one side of space and not the other, mirroring the human tendency to associate numbers with space. These and other studies confirmed that monkeys’ numerical decision-making follows similar patterns to that of humans, making them a good model for investigations of the neurobiological basis of numerical decision-making. </p><p>We sought to develop a system for exploring the neuronal basis of the cognitive and behavioral effects observed following transcranial magnetic stimulation, a relatively new, non-invasive method of brain stimulation that may be used to treat clinical disorders. We completed a set of pilot studies applying offline low-frequency repetitive transcranial magnetic stimulation to the macaque posterior parietal cortex, which has been implicated in numerical processing, while subjects performed a numerical comparison and control color comparison task, and while electrophysiological activity was recorded from the stimulated region of cortex. We found tentative evidence in one paradigm that stimulation did selectively impair performance in the number task, causally implicating the posterior parietal cortex in numerical decisions. In another paradigm, however, we manipulated the subject’s reaching behavior but not her number or color comparison performance. We also found that stimulation produced variable changes in neuronal firing and local field potentials. Together these findings lay the groundwork for detailed investigations into how different parameters of transcranial magnetic stimulation can interact with cortical architecture to produce various cognitive and behavioral changes.</p><p>Finally, we explored how monkeys decide how to behave in competitive social interactions. In a zero-sum computer game in which two monkeys played as a shooter or a goalie during a hockey-like “penalty shot” scenario, we found that shooters developed complex movement trajectories so as to conceal their intentions from the goalies. Additionally, we found that neurons in the dorsolateral and dorsomedial prefrontal cortex played a role in generating this “deceptive” behavior. We conclude that these regions of prefrontal cortex form part of a circuit that guides decisions to make an individual less predictable to an opponent.</p> / Dissertation