Cortical Activation Changes during Repeated Laser Stimulation: A Magnetoencephalographic Study

Repeated warm laser stimuli produce a progressive increase of the sensation of warmth and heat and eventually that of a burning pain. The pain resulting from repetitive warm stimuli is mediated by summated C fibre responses. To shed more light on the cortical changes associated with pain during repeated subnoxious warm stimution, we analysed magnetoencephalographic (MEG) evoked fields in eleven subjects during application of repetitive warm laser stimuli to the dorsum of the right hand. One set of stimuli encompassed 10 laser pulses occurring at 2.5 s intervals. Parameters of laser stimulation were optimised to elicit a pleasant warm sensation upon a single stimulus with a rise of skin temperature after repeated stimulation not exceeding the threshold of C mechano-heat fibres. Subjects reported a progressive increase of the intensity of heat and burning pain during repeated laser stimulation in spite of only mild (4.8°C) increase of skin temperature from the first stimulus to the tenth stimulus. The mean reaction time, evaluated in six subjects, was 1.33 s, confirming involvement of C fibres. The neuromagnetic fields were modelled by five equivalent source dipoles located in the occipital cortex, cerebellum, posterior cingulate cortex, and left and right operculo-insular cortex. The only component showing statistically significant changes during repetitive laser stimulation was the late component of the contralateral operculo-insular source peaking at 1.05 s after stimulus onset. The amplitude increases of the late component of the contralateral operculo-insular source dipole correlated with the subjects' numerical ratings of warmth and pain. Results point to a pivotal role of the contralateral operculo-insular region in processing of C-fibre mediated pain during repeated subnoxious laser stimulation

Tactile Modulation of the Sensory and Cortical Responses Elicited by Focal Cooling in Humans and Mice

Distinct sensory receptors transduce thermal and mechanical energies, but we have unified, coherent thermotactile experiences of the objects we touch. These experiences must emerge from the interaction of thermal and tactile signals within the nervous system. How do thermal and mechanical signals modify each other as they interact along the pathway from skin to conscious experience? In this thesis, we study how mechanical touch modulates cooling responses by combining psychophysics in humans and neural recordings in rodents. For this, we developed a novel stimulator to deliver focal, temperature-controlled cooling without touch. First, we used this method to study in humans the sensitivity to focal cooling with and without touch. We found that touch reduces the sensitivity to near-threshold cooling, which is perhaps analogous to the well-established ‘gating’ of pain by touch. Second, we studied the perceived intensity of cooling with and without touch. We found that tactile input enhances the perceived intensity of cooling. Third, we measured the responses of the mouse primary somatosensory cortex to cooling and mechanical stimuli using imaging and electrophysiological methods. We found multisensory stimuli elicited non-linear cortical responses at both the population and cellular level. Altogether, in this thesis, we show perceptual and cortical responses to non-tactile cooling for the first time. Based on our observations, we propose a new model to explain the interactions between cooling and mechanical signals in the nervous system. This thesis advances our understanding of how touch modulates cold sensations during thermotactile stimulation

Bidirectional alterations in brain temperature profoundly modulate spatiotemporal neurovascular responses in-vivo

Neurovascular coupling (NVC) is a mechanism that, amongst other known and latent critical functions, ensures activated brain regions are adequately supplied with oxygen and glucose. This biological phenomenon underpins non-invasive perfusion-related neuroimaging techniques and recent reports have implicated NVC impairment in several neurodegenerative disorders. Yet, much remains unknown regarding NVC in health and disease, and only recently has there been burgeoning recognition of a close interplay with brain thermodynamics. Accordingly, we developed a novel multi-modal approach to systematically modulate cortical temperature and interrogate the spatiotemporal dynamics of sensory-evoked NVC. We show that changes in cortical temperature profoundly and intricately modulate NVC, with low temperatures associated with diminished oxygen delivery, and high temperatures inducing a distinct vascular oscillation. These observations provide novel insights into the relationship between NVC and brain thermodynamics, with important implications for brain-temperature related therapies, functional biomarkers of elevated brain temperature, and in-vivo methods to study neurovascular coupling

A Rapid Sound-Action Association Effect in Human Insular Cortex

BACKGROUND: Learning to play a musical piece is a prime example of complex sensorimotor learning in humans. Recent studies using electroencephalography (EEG) and transcranial magnetic stimulation (TMS) indicate that passive listening to melodies previously rehearsed by subjects on a musical instrument evokes differential brain activation as compared with unrehearsed melodies. These changes were already evident after 20–30 minutes of training. The exact brain regions involved in these differential brain responses have not yet been delineated. METHODOLOGY/PRINCIPAL FINDING: Using functional MRI (fMRI), we investigated subjects who passively listened to simple piano melodies from two conditions: In the ‘actively learned melodies’ condition subjects learned to play a piece on the piano during a short training session of a maximum of 30 minutes before the fMRI experiment, and in the ‘passively learned melodies’ condition subjects listened passively to and were thus familiarized with the piece. We found increased fMRI responses to actively compared with passively learned melodies in the left anterior insula, extending to the left fronto-opercular cortex. The area of significant activation overlapped the insular sensorimotor hand area as determined by our meta-analysis of previous functional imaging studies. CONCLUSIONS/SIGNIFICANCE: Our results provide evidence for differential brain responses to action-related sounds after short periods of learning in the human insular cortex. As the hand sensorimotor area of the insular cortex appears to be involved in these responses, re-activation of movement representations stored in the insular sensorimotor cortex may have contributed to the observed effect. The insular cortex may therefore play a role in the initial learning phase of action-perception associations

Assessing Neuronal Synchrony and Brain Function Through Local Field Potential and Spike Analysis

Studies of neuronal network oscillations and rhythmic neuronal synchronization have led to a number of important insights in recent years, giving us a better understanding of the temporal organization of neuronal activity related to essential brain functions like sensory processing and cognition. Important principles and theories have emerged from these findings, including the communication through coherence hypothesis, which proposes that synchronous oscillations render neuronal communication effective, selective, and precise. The implications of such a theory may be universal for brain function, as the determinants of neuronal communication inextricably shape the neuronal representation of information in the brain. However, the study of communication through coherence is still relatively young. Since its articulation in 2005, the theory has predominantly been applied to assess cortical function and its communication with downstream targets in different sensory and behavioral conditions. The results herein are intended to bolster this hypothesis and explore new ways in which oscillations coordinate neuronal communication in distributed regions. This includes the development of new analytic tools for interpreting electrophysiological patterns, inspired by phase synchronization and spike train analysis. These tools aim to offer fast results with clear statistical and physiological interpretation

Magnetoencephalography

This is a practical book on MEG that covers a wide range of topics. The book begins with a series of reviews on the use of MEG for clinical applications, the study of cognitive functions in various diseases, and one chapter focusing specifically on studies of memory with MEG. There are sections with chapters that describe source localization issues, the use of beamformers and dipole source methods, as well as phase-based analyses, and a step-by-step guide to using dipoles for epilepsy spike analyses. The book ends with a section describing new innovations in MEG systems, namely an on-line real-time MEG data acquisition system, novel applications for MEG research, and a proposal for a helium re-circulation system. With such breadth of topics, there will be a chapter that is of interest to every MEG researcher or clinician

On-scalp MEG using high-Tc SQUIDs: Measuring brain activity with superconducting magnetometers

This thesis describes work done towards realizing on-scalp magnetoencephalography (MEG) based on high critical temperature (high-Tc) superconducting quantum interference device (SQUID) sensors. MEG is a non-invasive neuroimaging modality that records the magnetic fields produced by neural currents with good spatial and high temporal resolution. However, state-of-the-art MEG is limited by the use of liquid helium-cooled sensors (T ~ 4 K). The amount of thermal insulation between the sensors and the subject\u27s head that is required to achieve the extreme temperature difference (~300 K), typically realized in the form of superinsulation foil and ~2 centimeters of vacuum, limits measurable signals. Replacing the sensors with high-Tc SQUIDs can mitigate this problem. High-Tc SQUIDs operate at much higher temperatures (90 K) allowing significant reduction of the stand-off distance (to ~1 mm). They can furthermore be cooled with liquid nitrogen (77 K), a cheaper, more sustainable alternative to the liquid helium used for cooling in conventional MEG systems.The work described in this thesis can be divided into three main areas: (I) simulation work for practical implementations of on-scalp systems, (II) development of a 7-channel high-Tc SQUID-based on-scalp MEG system, and (III) on-scalp MEG recordings.In the first part, spatial information density (SID), a metric to evaluate the performance of simulated MEG sensor arrays, is introduced and - along with total information capacity - used to compare the performance of various simulated full-head on-scalp MEG sensor arrays.\ua0Simulations demonstrate the potential of on-scalp MEG, with all on-scalp systems exhibiting higher information capacity than the state-of-the-art. SID further reveals more homogeneous sampling of the brain with flexible systems. A method for localizing magnetometers in on-scalp MEG systems is introduced and tested in simulations. The method uses small, magnetic dipole-like coils to determine the location and orientation of individual sensors, enabling straightforward co-registration in flexible on-scalp MEG systems. The effects of different uncertainties and errors on the accuracy of the method were quantified.In the second part, design, construction, and performance of a 7-channel on-scalp MEG system is described. The system houses seven densely-packed (2 mm edge-to-edge), head-aligned high-Tc SQUID magnetometers (9.2 mm x 8.6 mm) inside a single, liquid nitrogen-cooled cryostat. With a single filling, the system can be utilized for MEG recordings for >16 h with low noise levels (~0-130 fT). Using synchronized clocks and a direct injection feedback scheme, the system achieves low sensor crosstalk (<0.6%).\ua0In the third part, on-scalp MEG recordings with the 7-channel system as well as its predecessor, a single-channel system, are presented. The recordings are divided into proof-of-principle and benchmarking experiments. The former consist of well-studied, simple paradigms such as auditory evoked activity and visual alpha. Expected signal components were clearly seen in the on-scalp recordings. The benchmarking studies were done to compare and contrast on-scalp with state-of-the-art MEG. To this end, a number of experimental stimulus paradigms were recorded on human subjects with the high-Tc SQUID-based on-scalp systems as well as a state-of-the-art, commercial full-head MEG system. Results include the expected signal gains that are associated with recording on-scalp as well as new details of the neurophysiological signals. Using the previously described on-scalp MEG co-registration method enabled source localization with high agreement to the full-head recording (the distance between dipoles localized with the two systems was 4.2 mm)