Multimodal characterisation of sensorimotor oscillations

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

The utility of Magnetoencephalography in multiple sclerosis – A systematic review

Introduction: Magnetoencephalography (MEG), allows for a high degree temporal and spatial accuracy in recording cortical oscillatory activity and evoked fields. To date, no review has been undertaken to synthesise all MEG studies in Multiple Sclerosis (MS). We undertook a Systematic Review of the utility of MEG in MS. / Methods: We identified MEG studies carried out in MS using EMBASE, Medline, Cochrane, TRIP and Psychinfo databases. We included original research articles with a cohort of minimum of five multiple sclerosis patients and quantifying of at least one MEG parameter. We used a modified version of the JBI (mJBI) for case-control studies to assess for risk of bias. / Results: We identified 30 studies from 13 centres involving at least 433 MS patients and 347 controls. We found evidence that MEG shows perturbed activity (most commonly reduced power modulations), reduced connectivity and association with altered clinical function in Multiple Sclerosis. Specific replicated findings were decreased motor induced responses in the beta band, diminished increase of gamma power after visual stimulation, increased latency and reduced connectivity for somatosensory evoked fields. There was an association between upper alpha connectivity and cognitive measures in people with MS. Overall studies were of moderate quality (mean mJBI score 6.7). / Discussion: We find evidence for the utility of MEG in Multiple Sclerosis. Event-related designs are of particular value and show replicability between centres. At this stage, it is not clear whether these changes are specific to Multiple Sclerosis or are also observable in other diseases. Further studies should look to explore cognitive control in more depth using in-task designs and undertake longitudinal studies to determine whether these changes have prognostic value

Neuromagnetic investigations of mechanisms and effects of STN-DBS and medication in Parkinson's disease

Parkinson’s disease (PD) is a neurodegenerative disorder cardinally marked by motor symptoms, but also sensory symptoms and several other non-motor symptoms. PD patients are typically treated with dopaminergic medication for several years. Many patients eventually experience bouts of periods where medication might not be able to effectively control symptoms as well as experience side-effects of long-term dopaminergic treatments. Deep brain stimulation (DBS) is an option as the next therapeutic recourse for such patients. DBS treatment essentially involves placement of stimulating electrodes in the subthalamic nucleus (STN) or the globus pallidus internum (GPi) along with an implanted pulse generator (IPG) in the sub-clavicular space. STN-DBS alleviates motor symptoms and leads to substantial improvements in quality of life for PD patients. Although DBS is known to improve several classes of symptoms, the effect mechanism of DBS is still not clear. While there is a lack of electrophysiological investigation of sensory processing and the effects of treatments in PD altogether, the electrophysiological studies of the cortical dynamics during motor tasks and at rest lack consensus.We recorded magnetoencephalography (MEG) and electromyography (EMG) from PD patients in three studies: (i) at rest, (ii) during median nerve stimulation, and (iii) while performing phasic contractions (hand gripping). The three studies focused on cortical oscillatory dynamics at rest, during somatosensory processing and during movement, respectively. The measurements were conducted in DBS-treated, untreated (DBS washout) and dopaminergic-medicated states. While both treatments (DBS and dopaminergic medication) ameliorated motor symptoms similarly in all studies, they showed differentiated effects on: (i) increased sensorimotor cortical low-gamma spectral power (31-45 Hz) (but no changes in beta power (13-30 Hz)) at rest only during DBS, (ii) somatosensory processing with higher gamma augmentation (31-45 Hz, 20-60 ms) in the dopaminergic-medicated state compared to DBS-treated and untreated states, and (iii) hand gripping with increased motor-related beta corticomuscular coherence (CMC, 13-30 Hz) during dopaminergic medication in contrast to increased gamma power (31-45 Hz) during DBS.Firstly, we infer from the three studies that DBS and dopaminergic medication employ partially different anatomo-functional pathways and functional strategies when improving PD symptoms. Secondly, we suggest that treatments act on pathological oscillatory dynamics differently at cortical and sub-cortical levels and may do so through more sophisticated mechanisms than mere suppression of the pathological spectral power in a particular band. And thirdly, we urge exploring effect mechanisms of PD treatments beyond the motor system. The effects of dopaminergic medication on early somatosensory processing has opened the door for exploring the effects of treatments and studying their mechanisms using electrophysiology, especially in higher order sensory deficits. Integration of such research findings into a holistic view on mechanisms of treatments could pave way for better disease management paradigms. 

Reduction of somatosensory functional connectivity by transcranial alternating current stimulation at endogenous mu-frequency

Alpha, the most prominent human brain rhythm, might reflect a mechanism of functional inhibition for gating neural processing. This concept has been derived predominantly from local measures of inhibition, while large-scale network mechanisms to guide information flow are largely unknown. Here, we investigated functional connectivity changes on a whole-brain level by concurrent transcranial alternating current stimulation (tACS) and resting-state functional MRI in humans. We specifically focused on somatosensory alpha-band oscillations by adjusting the tACS frequency to each individual´s somatosensory (mu-) alpha peak frequency (mu-tACS). Potential differences of Eigenvector Centrality of primary somatosensory cortex (S1) as well as on a whole brain level between mu-tACS and sham were analyzed. Our results demonstrate that mu-tACS induces a locally-specific decrease in whole-brain functional connectivity of left S1. An additional exploratory analysis revealed that this effect primarily depends on a decrease in functional connectivity between S1 and a network of regions that are crucially involved in somatosensory processing. Furthermore, the decrease in functional centrality was specific to mu-tACS and was not observed when tACS was applied in the gamma-range in an independent study. Our findings provide evidence that modulated somatosensory (mu-) alpha-activity may affect whole-brain network level activity by decoupling primary sensory areas from other hubs involved in sensory processing

Neuronal oscillations in gamma- and alpha-frequency bands : from object representations to sensory awareness

The synchronization of neuronal activity, especially in the beta- (14-30 Hz) /gamma- (30 80 Hz) frequency bands, is thought to provide a means for the integration of anatomically distributed processing and for the formation of transient neuronal assemblies. Thus non-stimulus locked (i.e. induced) gamma-band oscillations are believed to underlie feature binding and the formation of neuronal object representations. On the other hand, the functional roles of neuronal oscillations in slower theta- (4 8 Hz) and alpha- (8 14 Hz) frequency bands remain controversial. In addition, early stimulus-locked activity has been largely ignored, as it is believed to reflect merely the physical properties of sensory stimuli. With human neuromagnetic recordings, both the functional roles of gamma- and alpha-band oscillations and the significance of early stimulus-locked activity in neuronal processing were examined in this thesis. Study I of this thesis shows that even the stimulus-locked (evoked) gamma oscillations were sensitive to high-level stimulus features for speech and non-speech sounds, suggesting that they may underlie the formation of early neuronal object representations for stimuli with a behavioural relevance. Study II shows that neuronal processing for consciously perceived and unperceived stimuli differed as early as 30 ms after stimulus onset. This study also showed that the alpha band oscillations selectively correlated with conscious perception. Study III, in turn, shows that prestimulus alpha-band oscillations influence the subsequent detection and processing of sensory stimuli. Further, in Study IV, we asked whether phase synchronization between distinct frequency bands is present in cortical circuits. This study revealed prominent task-sensitive phase synchrony between alpha and beta/gamma oscillations. Finally, the implications of Studies II, III, and IV to the broader scientific context are analysed in the last study of this thesis (V). I suggest, in this thesis that neuronal processing may be extremely fast and that the evoked response is important for cognitive processes. I also propose that alpha oscillations define the global neuronal workspace of perception, action, and consciousness and, further, that cross-frequency synchronization is required for the integration of neuronal object representations into global neuronal workspace.Tässä väitöskirjassa tutkittiin aivojen rytmistä toimintaa ja sen merkitystä ärsykkeistä muodostettaviin hermostollisiin esityksiin ja tietoiseen havaintoon. Aivo-oskillaatioita tutkittiin magnetoenkefalografialla (MEG) rekisteröimällä pään pinnalta erittäin pieniä aivojen sähköisen toiminnan aiheuttamia magneettikentän muutoksia. Väitöskirjan ensimmäisessä osatyössä koehenkilöille esitettiin kielellisiä ja ei-kielellisiä ärsykkeitä. Havaittiin, että ärsykettä seuraavat nopeat gammaoskillaatiot erosivat kielellisille ja ei kielellisille ärsykkeille. Pääteltiin, että gammaoskillaatiot voivat heijastaa ärsykkeistä muodostettavaa hermostollista esitystä ja että kielellisten ja ei kielellisten ärsykkeiden käsittely eroaa jo hyvin varhaisessa vaiheessa noin 40 ms ärsykkeen alun jälkeen. Väitöskirjan toisessa osatyössä tutkittiin tietoisen havainnon muodostumista hyvin heikoille tuntoärsykkeille, jotka toisinaan havaittiin, ja jotka toisinaan jäivät havaitsematta. Havaittuja tuntoärsykkeitä seurasi alfaoskillaation vaihelukittuminen ärsykkeeseen, mutta jos ärsykettä ei havaittu, alfaoskillaatioiden vaihelukittumista ärsykkeeseen ei tapahtunut. Alfaoskillaatioiden vaihelukittuminen korreloi siis tietoisen havainnon kanssa. Väitöskirjan kolmannessa osatyössä tutkittiin ärsykettä edeltävän rytmisen aivotoiminnan vaikutusta tietoisen havainnon syntyyn hyvin heikoille tuntoärsykkeille. Havaittiin, että heikko tuntoärsyke havaitaan parhaiten, jos ärsykettä edeltävät aivo-oskillaatiot ovat suuruudeltaan keskisuuria, mutta että jos ärsykettä edeltävät aivo-oskillaatiot ovat voimakkuudeltaan joko suuria tai pieniä, heikko tuntoärsyke havaitaan harvemmin. Väitöskirjan neljännessä osatyössä tutkittiin eri taajuisten aivo-oskillaatioiden välistä synkroniaa levon ja työmuistia vaativan päässälaskutehtävän aikana. Havaittiin, että päässälaskutehtävän aikana alfa ja gamma taajuiset oskillaatiot synkronoituivat enemmän kuin levon aikana. Tämän ehdotettiin mahdollistavan alfa ja gamma oskillaatioiden välisen vuorovaikutuksen eli alfa ja gamma oskillaatioiden toiminnallisten roolien integroinnin. Väitöskirjan viimeisessä osatyössä muodostettiin synteesi erityisesti alfa oskillaatioiden toiminnallisesta roolista tietoisen havainnon aikana. Ehdotettiin, että gamma oskillaatiot heijastavat ärsykkeistä muodostettavia hermostollisia esityksiä, mutta että alfa oskillaatiot heijastavat itse tietoista havaintoa. Ehdotettiin, että alfa ja gamma oskillaatioiden toiminnalliset roolit voidaan integroida taajuuksien välisen synkronian avulla, mikä mahdollistaisi mm. tietoisen havainnon synnyn sekä objekti representaatioiden ylläpidon työmuistin aikana

Electrical stimulation of the ear, head, cranial nerve, or cortex for the treatment of tinnitus: a scoping review

Tinnitus is defined as the perception of sound in the absence of an external source. It is often associated with hearing loss and is thought to result from abnormal neural activity at some point or points in the auditory pathway, which is incorrectly interpreted by the brain as an actual sound. Neurostimulation therapies therefore, which interfere on some level with that abnormal activity, are a logical approach to treatment. For tinnitus, where the pathological neuronal activity might be associated with auditory and other areas of the brain, interventions using electromagnetic, electrical, or acoustic stimuli separately, or paired electrical and acoustic stimuli, have been proposed as treatments. Neurostimulation therapies should modulate neural activity to deliver a permanent reduction in tinnitus percept by driving the neuroplastic changes necessary to interrupt abnormal levels of oscillatory cortical activity and restore typical levels of activity. This change in activity should alter or interrupt the tinnitus percept (reduction or extinction) making it less bothersome. Here we review developments in therapies involving electrical stimulation of the ear, head, cranial nerve, or cortex in the treatment of tinnitus which demonstrably, or are hypothesised to, interrupt pathological neuronal activity in the cortex associated with tinnitus

A model of delta frequency neuronal network activity and theta-gamma interactions in rat sensorimotor cortex in vitro

In recent decades, advances in electrophysiological techniques have enabled understanding of neuronal network activity, with in vitro brain slices providing insights into the mechanisms underlying oscillations at various frequency ranges. Understanding the electrical and neuro-pharmacological properties of brain networks using selective receptor modulators in native tissue allows to compare such properties with those in disease models (e.g. epilepsy and Parkinson’s). In vivo and in vitro studies have implicated M1 in execution of voluntary movements and, from both local network in vitro and whole brain in vivo perspectives. M1 has been shown to generate oscillatory activity at various frequencies, including beta frequency and nested theta and gamma oscillations similar to those of rat hippocampus. In vivo studies also confirmed slow wave oscillations in somatosensory cortex including delta and theta band activity. However, despite these findings, non-thalamic mechanisms underlying cortical delta oscillations remain almost unexplored. Therefore, we determined to explore these oscillations in vitro in M1 and S1. Using a modified sagittal plane slice preparation with aCSF containing neuroprotectants, we have greatly improved brain slice viability, enabling the generation and study of dual rhythms (theta and gamma oscillations) in deep layers (LV) of the in vitro sensorimotor slice (M1 and S1) in the presence of KA and CCh. We found that theta-gamma activity in M1 is led by S1 and that the amplitude of gamma oscillations was (phase-amplitude) coupled to theta phase in both regions. Oscillations were dependent on GABAAR, AMPAR and NMDAR and were augmented by DAR activation. Experiments using cut/reduced slices showed both M1 and S1 could be intrinsic generators of oscillatory activity. Delta oscillations were induced in M1 and S1 by maintaining a neuromodulatory state mimicking deep sleep, characterised by low dopaminergic and low cholinergic tone, achieved using DAR blockade and low CCh. Delta activity depends on GABAAR, GABABR and AMPAR but not NMDAR, and once induced was not reversible. Unlike theta-gamma activity, delta was led by M1, and activity took >20mins to develop in S1 after establishement of peak power in M1. Unlike M1, S1 alone was unable to support delta activity. Dopamine modulates network activity in M1 and it is known that fast-spiking interneurons are the pacemakers of network rhythmogenesis. Recent studies reported that dopamine (DA) controled Itonic in medium spiny, ventrobasal thalamus and nucleus accumbens neurons by modulation of GABARs or cation channels. In the current study, voltage-clamp whole cell recordings were performed in fast spiking interneurons (FS cells) in Layer V of M1. These recordings revealed tonic and phasic GABAAR inhibition and when DA was bath applied, a slow inward current (IDA) was induced. IDA was mediated by non-specific cationic TRPC channels following D2R-like receptor activation. Overall, my studies show the strong interdependence of theta-gamma rhythmogenesis between M1 and S1, dominanace of M1 at delta frequency and the crucial role of dopamine in controlling FS cell activity. Further exploration of these rhythms in models of pathological conditions such as Parkinson`s disease and Epilepsy may provide insights into network changes underlying these disease conditions