Executive "brake failure" following deactivation of human frontal lobe

In the course of daily living, humans frequently encounter situations in which a motor activity, once initiated, becomes unnecessary or inappropriate. Under such circumstances, the ability to inhibit motor responses can be of vital importance. Although the nature of response inhibition has been studied in psychology for several decades, its neural basis remains unclear. Using transcranial magnetic stimulation, we found that temporary deactivation of the pars opercularis in the right inferior frontal gyrus selectively impairs the ability to stop an initiated action. Critically, deactivation of the same region did not affect the ability to execute responses, nor did it influence physiological arousal. These findings confirm and extend recent reports that the inferior frontal gyrus is vital for mediating response inhibition

PreSMA stimulation changes task-free functional connectivity in the fronto-basal-ganglia that correlates with response inhibition efficiency

Previous work using transcranial magnetic stimulation (TMS) demonstrated that the right pre-supplementary motor area (preSMA), a node in the fronto-basal-ganglia network, is critical for response inhibition. However, TMS influences interconnected regions, raising the possibility of a link between the preSMA activity and the functional connectivity within the network. To understand this relationship, we applied single-pulse TMS to the right preSMA during functional magnetic resonance imaging when the subjects were at rest to examine changes in neural activity and functional connectivity within the network in relation to the efficiency of response inhibition evaluated with a stop-signal task. The results showed that preSMA-TMS increased activation in the right inferior-frontal cortex (rIFC) and basal ganglia and modulated their task-free functional connectivity. Both the TMS-induced changes in the basal-ganglia activation and the functional connectivity between rIFC and left striatum, and of the overall network correlated with the efficiency of response inhibition and with the white-matter microstructure along the preSMA – rIFC pathway. These results suggest that the task-free functional and structural connectivity between the rIFCop and basal ganglia are critical to the efficiency of response inhibition

Effects of rTMS of pre-supplementary motor area on fronto basal ganglia network activity during stop-signal task

Stop-signal task (SST) has been a key paradigm for probing human brain mechanisms underlying response inhibition, and the inhibition observed in SST is now considered to largely depend on a fronto basal ganglia network consisting mainly of right inferior frontal cortex, pre-supplementary motor area (pre-SMA), and basal ganglia, including subthalamic nucleus, striatum (STR), and globus pallidus pars interna (GPi). However, causal relationships between these frontal regions and basal ganglia are not fully understood in humans. Here, we partly examined these causal links by measuring human fMRI activity during SST before and after excitatory/inhibitory repetitive transcranial magnetic stimulation (rTMS) of pre-SMA. We first confirmed that the behavioral performance of SST was improved by excitatory rTMS and impaired by inhibitory rTMS. Afterward, we found that these behavioral changes were well predicted by rTMS-induced modulation of brain activity in pre-SMA, STR, and GPi during SST. Moreover, by examining the effects of the rTMS on resting-state functional connectivity between these three regions, we showed that the magnetic stimulation of pre-SMA significantly affected intrinsic connectivity between pre-SMA and STR, and between STR and GPi. Furthermore, the magnitudes of changes in resting-state connectivity were also correlated with the behavioral changes seen in SST. These results suggest a causal relationship between pre-SMA and GPi via STR during response inhibition, and add direct evidence that the fronto basal ganglia network for response inhibition consists of multiple top-down regulation pathways in humans

Action control in uncertain environments

A long-standing dichotomy in neuroscience pits automatic or reflexive drivers of behaviour against deliberate or reflective processes. In this thesis I explore how this concept applies to two stages of action control: decision-making and response inhibition. The first part of this thesis examines the decision-making process itself during which actions need to be selected that maximise rewards. Decisions arise through influences from model-free stimulus-response associations as well as model-based, goal-directed thought. Using a task that quantifies their respective contributions, I describe three studies that manipulate the balance of control between these two systems. I find that a pharmacological manipulation with levodopa increases model-based control without affecting model-free function; disruption of dorsolateral prefrontal cortex via magnetic stimulation disrupts model-based control; and direct current stimulation to the same prefrontal region has no effect on decision-making. I then examine how the intricate anatomy of frontostriatal circuits subserves reinforcement learning using functional, structural and diffusion magnetic resonance imaging (MRI). A second stage of action control discussed in this thesis is post-decision monitoring and adjustment of action. Specifically, I develop a response inhibition task that dissociates reactive, bottom-up inhibitory control from proactive, top-down forms of inhibition. Using functional MRI I show that, unlike the strong neural segregation in decision-making systems, neural mechanisms of reactive and proactive response inhibition overlap to a great extent in their frontostriatal circuitry. This leads to the hypothesis that neural decline, for 4 example in the context of ageing, might affect reactive and proactive control similarly. I test this in a large population study administered through a smartphone app. This shows that, against my prediction, reactive control reliably declines with age but proactive control shows no such decline. Furthermore, in line with data on gender differences in age-related neural degradation, reactive control in men declines faster with age than that of women

Theta burst magnetic stimulation over the pre-supplementary motor area improves motor inhibition

BACKGROUND: Stopping an ongoing motor response or resolving conflict induced by conflicting stimuli are associated with activation of a right-lateralized network of inferior frontal gyrus (IFG), pre-supplementary motor area (pre-SMA) and subthalamic nucleus (STN). However, the roles of the right IFG and pre-SMA in stopping a movement and in conflict resolution remain unclear. We used continuous theta burst stimulation (cTBS) to examine the involvement of the right IFG and pre-SMA in inhibition and conflict resolution using the conditional stop signal task. METHODS: We measured stop signal reaction time (SSRT, measure of reactive inhibition), response delay effect (RDE, measure of proactive action restraint) and conflict induced slowing (CIS, measure of conflict resolution). RESULTS: Stimulation over the pre-SMA resulted in significantly shorter SSRTs (improved inhibition) compared to sham cTBS. This effect was not observed for CIS, RDE, or any other measures. cTBS over the right IFG had no effect on SSRT, CIS, RDE or on any other measure. CONCLUSIONS: The improvement of SSRT with cTBS over the pre-SMA suggests its critical contribution to stopping ongoing movements

Transcranial Magnetic Stimulation and Neuroimaging Coregistration

The development of neuroimaging techniques is one of the most impressive advancements in neuroscience. The main reason for the widespread use of these instruments lies in their capacity to provide an accurate description of neural activity during a cognitive process or during rest. This important advancement is related to the possibility to selectively detect changes of neuronal activity in space and time by means of different biological markers. Specifically, functional magnetic resonance imaging (fMRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and nearinfrared spectroscopy (NIRS) use metabolic markers of ongoing neuronal activity to provide an accurate description of the activation of specific brain areas with high spatial resolution. Similarly, electroencephalography (EEG) is able to detect electric markers of neuronal activity, providing an accurate description of brain activation with high temporal resolution. The application of these techniques during a cognitive task allows important inferences regarding the relation between the detected neural activity, the cognitive process involved in an ongoing task, and behaviour: this is known as a \u201ccorrelational approach\u201d

Cortical mapping of the neuronal circuits modulating the muscle tone. Introduction to the electrophysiological treatment of the spastic hand

L'objectiu d'aquest estudi es investigar l'organització cortical junt amb la connectivitat còrtico-subcortical en subjectes sans, com a estudi preliminar. Els mapes corticals s'han fet per TMS navegada, i els punts motors obtinguts s'han exportant per estudi tractogràfic i anàlisi de las seves connexions. El coneixement precís de la localització de l'àrea cortical motora primària i les seves connexions es la base per ser utilitzada en estudis posteriors de la reorganització cortical i sub-cortical en pacients amb infart cerebral. Aquesta reorganització es deguda a la neuroplasticitat i pot ser influenciada per els efectes neuromoduladors de la estimulació cerebral no invasiva.The purpose of this study is to investigate the motor cortex organisation together with the cortico-subcortical connectivity in healthy subjects, as a preliminary study. Cortical maps have been performed by navigated TMS and the motor points have been exported to DTI to study their subcortical connectivity. The precise knowledge of localization of the primary motor cortex area and its connectivity is the base to be used in later studies of cortical and subcortical re-organisation in stroke patients. This re-organisation is due to the neuroplascity and can be influenced by the neuromodulation effects of the non-invasive cerebral stimulation therapy by TMS

Investigating the efficacy of dual-site transcranial alternating current stimulation for alleviating age-related declines in response inhibition

Response inhibition, the ability to suppress or cancel a pre-potent motor action, is instrumental in the flexible adaptation of behaviour to an ever-changing external environment. Unfortunately, inhibitory performance deteriorates with ageing, which is detrimental to the functional independence of older adults. The main objective of this thesis was two-fold. Firstly, to ascertain if age-related declines in response inhibition can be ameliorated by transcranial alternating current stimulation (tACS), a form of non-invasive brain stimulation. Secondly, to gain mechanistic insight into the neurophysiological underpinnings of response inhibition in healthy older individuals. A narrative review (Chapter 1) was conducted to examine the available research evidence on the neural correlates of inhibitory performance. It was found that effective response inhibition performance is subserved by the functional connectivity between the right inferior frontal gyrus (rIFG) and the presupplementary motor area (preSMA), especially for neural activity at beta frequencies. The extant literature also indicates that dual-site tACS can exert facilitatory effects on the functional connectivity between brain regions. Specifically, in-phase tACS, which entails the delivery of currents at the same oscillatory phase to two target sites, was found to promote inter-regional connectivity. Conversely, anti-phase tACS, whereby the currents to the target sites are delivered at opposite phases, was found to weaken interregional connectivity. Therefore, it was deduced that the application of beta frequency inphase tACS over the rIFG and the preSMA could potentially mitigate age-related deficits in inhibitory performance. To test this hypothesis, a double-blind crossover study involving 18 healthy older adults and 15 younger older adults was carried out to elucidate the effects of in- and anti-phase beta tACS (1 mA; 20 min; applied at rest) on stop-signal task performance (Study 1: Chapters 2 to 5). In-phase tACS led to significant improvements in the action cancellation speeds of younger, but not older, individuals. Moreover, in-phase stimulation resulted in a significant brain-behaviour relationship between cancellation speed and resting-state rIFG-preSMA connectivity for younger participants only. The effects of tACS on inhibitory performance appeared to be contingent upon the endogenous beta-band phase angle difference between rIFG and preSMA during resting-state. Anti-phase tACS was also found to exert differential effects on cortico-cortical gamma-band coupling for older and younger individuals. However, these age-related differences in network connectivity were not reflected in inhibitory performance. tACS-induced changes in response inhibition performance also appeared to be independent of task-related rIFG-preSMA phase connectivity on the scalp- and cortical-level for both older and younger adults. A substantial inter-individual variability in tACS-induced neurophysiological outcomes was also detected, particularly for older participants. This suggests that there may be greater heterogeneity in the dose-response relationship of older adults, in comparison to their younger counterparts. Subsequently, electric field simulation modelling was conducted to explore how the current dosage of the dual-site tACS protocol could be modified to improve the intensity and focality of tACS-induced currents in the brain (Study 2: Chapter 6). It was found that higher field strengths are accompanied by poorer field focality to target sites, and that this strengthfocality trade-off must be considered when deciding on tACS current intensities. The current dosages of the tACS protocol utilised in Study 1 were revised in consideration of the findings of Study 2. A sham-controlled, double-blind, crossover study was conducted to test the efficacy of this modified tACS protocol (1.0 mA for rIFG, 1.6 mA for preSMA; 20 min) on improving the inhibitory performance of seven healthy older adults (Study 3: Chapter 7). The study also investigated if an ‘online’ approach, where tACS was administered during task performance, would be more efficacious than if tACS was applied ‘offline’, i.e., when participants were at rest and in a task-free state. Due to the small sample size, group-level and single-subject analyses were employed. The findings of Study 3 indicated that neither online nor offline tACS significantly improved stop-signal task performance. Furthermore, not only was cancellation speed not associated with beta-band phase-coupling between rIFG and preSMA during resting-state and task performance, their inter-regional phase connectivity was not a significant predictor of stop outcome, i.e., the success or failure of stop attempts. Instead, task-related gamma-band rIFG-preSMA phase-coupling was found to be a significant predictor of stop outcome. Changes in source-reconstructed cortio-cortical networks from pre- to post-sham stimulation were also indicative of potential fatigue-related changes in network connections – this is an important factor that future research will need to account for when studying tACS-induced changes in phase-coupling during task performance. Overall, the findings of this thesis suggest that rIFG-preSMA beta tACS was potentially efficacious in facilitating the inhibitory performance of healthy younger adults. However, its effects in healthy older individuals were subject to considerable heterogeneity. Despite the lack of clear evidence supporting the efficacy of this tACS protocol in alleviating age-related declines in response inhibition, the findings of this thesis have provided important insights into the neural underpinnings of inhibitory performance and contributed to a broader mechanistic understanding of the effects of dual-site tACS on functional connectivity