Ucl Institute of Neurology

s: Pharmaco-MEG and beta frequency neocortical oscillations Ian M. Stanford, School of Life and Health Sciences, Aston University, Birmingham UK Using pharmaco-magnetoencephalography (Hall et al., 2009) we have shown that specific cognitive and motor deficits relate to abnormally elevated slow-wave oscillatory activity in stroke and exaggerated beta frequency activity in Parkinson’s disease (PD) and that sub-sedative doses of the commonly administered as a sleeping tablet hypnotic drug zolpidem are able to reduce the power of these pathological oscillations. Study participant (JP) presented with major left hemispherical damage and impaired motor and language function. Substantial neuronal loss within the lesion and metabolic stress on peri-lesion cortical tissue was confirmed using SPECT, MRI and MRS. MEG revealed persistent pathological theta (4-10Hz) and beta (15-30Hz) activity in surviving sensorimotor and language areas, consistent with JP’s altered gait and speech agnosia. Zolpidem reduced the power of these oscillations in all regions of the lesioned hemisphere. This desynchronising effect correlated strongly with zolpidem uptake and was coincident with marked improvements in cognitive and motor function. Control experiments revealed no effect of placebo, while a structurally unrelated hypnotic, zopiclone, elicited widespread increases in cortical oscillatory power in the beta band without functional improvement. PD participant (CC) voluntarily underwent L-DOPA washout. CC presented with rigidity, bradykinesia and unilateral resting tremor. Analysis revealed elevated persistent beta2 oscillations (~27Hz) accompanied by oscillatory bursts of beta1 activity (~20Hz) in M1. The power of the beta1 oscillatory power was reduced following zolpidem administration. Desynchronisation was accompanied by CC’s perception of improved motor function and this was confirmed with a reduced UPDRS-III score. Thus, the specific activity patterns and oscillatory frequencies in M1 appear to correlate with motor deficits and elevation of low-frequency ‘burst’ activity in PD acts as a barrier to normal function. The ability of low-dose zolpidem to desynchronise such pathological low-frequency oscillatory activity, may reflect a unique action related to its specificity for GABAA receptors containing the α1 subunit. To test this hypothesis we have used we examined the properties of M1 network oscillations in coronal slices taken from rat brain. Extracellular population recordings in layer 5 revealed oscillatory beta activity (24.7±0.48Hz, n = 22) were elicited by co-application kainic acid (400nM) and carbachol (50μM). Initial studies showed an increase in oscillatory power in the presence of 100nM zolpidem (Yamawaki et al., 2008), which was in conflict with the clinical data. However, zolpidem was shown to create a bell-shaped dose response, increasing power at 30 and 100nM and decreasing power at concentrations of 10 and 500nM. Application of GABAA receptor partial agonist L-838,417 (100nM) which selectively binds to α2, α3 and α5 subunits but has no efficacy at the α1 subunit induced a marked increase in oscillatory power. Subsequent addition of 10nM zolpidem reduced the oscillatory power. These results suggest that the sub-sedative doses of zolpidem used in the clinical studies are likely to be α1-subunit selective, working at concentrations less than 30nM to cause the neuronal desynchronisation. Hall SD., Barnes GR., Furlong PL., Seri S, Hillebrand A. (2009). Neuronal network pharmacodynamics of GABAergic modulation in the human cortex determined using pharmaco-magnetoencephalography. Human Brain Mapping (in press). Yamawaki N., Stanford IM., Hall SD., Woodhall GL (2008) Pharmacological induced and stimulus evoked rhythmic neuronal oscillatory activity in the primary motor cortex (M1) in vitro. Neurosci. 151, 386-395. Using TMS to influence rhythmic brain activity Gregor Thut, Dept of Psychology, University of Glasgow, UK Both transcranial magnetic stimulation (TMS) and neuronal interactions share a common dimension. TMS can be used to stimulate the brain in rhythmic pulse-trains. And, neuronal elements functionally assemble through synchronization in distinct frequency bands, giving rise to brain rhythms. This raises the question whether rhythmic TMS could be used to interact with the brain in its own way of communication? I will provide a short introduction of how to influence rhythmic brain activity via TMS, illustrated through findings from TMS-EEG studies and focusing on the alpha-band. My talk will cover offline aftereffects [1], online interference [2], online induction [3], and online interaction/entrainment [unpublished data] with/of ongoing brain oscillations [4]. Many of the reported effects on neuronal oscillations by TMS (online and offline) are not frequencyspecific (because spreading to other bands than the stimulation-frequency), and hence seem to be secondary to rTMS-induced neurophysiologic changes. However, there are recent reports of frequency-specific behavioural effects by rhythmic TMS (online) that only occur when the brain has been stimulated at the target area?s supposed natural frequency (but not at other frequencies). This is suggestive of entrainment of ongoing oscillations. Rhythmic brain activity may hence not only be used to infer momentary brain states. It is conceivable that rhythmic brain activity can also transiently be induced by TMS to alter brain states and thus functions in desired directions. Thut G, Pascual-Leone A. A Review of Combined TMS-EEG Studies to Characterize Lasting Effects of Repetitive TMS and Assess Their Usefulness in Cognitive and Clinical Neuroscience. Brain Topogr. 2009 Capotosto P, Babiloni C, Romani GL, Corbetta M. Frontoparietal cortex controls spatial attention through modulation of anticipatory alpha rhythms. J Neurosci 2009 29: 5863-72. Rosanova M, Casali A, Bellina V, Resta F, Mariotti M, Massimini M. Natural frequencies of human corticothalamic circuits. J Neurosci 2009 29: 7679-85. Thut G, Miniussi C. New insights into rhythmic brain activity from TMS-EEG studies. Trends Cogn Sci 2009 13: 182-9. Oscillations in memory and sleep Nikolai Axmacher, Department of Epileptology, University of Bonn, Germany Information processing in the brain does not only depend on the rate of action potentials, but also on their precise timing. Recent studies showed that due to a locking of action potentials to a specific phase of oscillatory activity, neural oscillations serve to facilitate communication between synchronized brain regions. Moreover, oscillatory activity may define time windows for spike-timing dependent forms of synaptic plasticity and thereby facilitate learning and memory formation. This talk provides an overview on intracranial EEG studies on the role of oscillations during different memory processes. Long-term memory formation is accompanied by an increase in phase synchronization between rhinal cortex and hippocampus. Facilitated encoding of unexpected information relies on a loop involving the hippocampus and nucleus accumbens. During working memory (WM), we observed slow potentials in the medial temporal lobe (MTL) and a load-dependent increase in gamma band activity in the rhinal cortex. Interactions between face-selective regions in the inferior temporal cortex and the MTL and within the latter one increased with memory load, indicating an enhanced MTL recruitment during maintenance of multiple items. Furthermore, WM maintenance was associated with an enhanced locking of gamma power to specific phases of theta cycles, consistent with an influential model of the mechanism underlying multi-item WM. During sleep, high-frequent “ripple” activity in the rhinal cortex correlated with subsequent retrieval, indicative of a role of these oscillations for memory consolidation. Finally, we found that ripples were followed by an enhanced synchronization between MTL and neocortex, possibly related to information transfer during sleep. Taken together, these findings indicate that oscillatory activities in different frequency bands play a role during different steps of memory formation. Axmacher, N., Mormann,. F., Fernández, G., Elger, C.E. and Fell, J. (2006) Memory formation by neuronal synchronization. Brain Res Rev. 52(1): 170-182. Axmacher, N., Schmitz, D.P., Wagner, T., Elger C.E. and Fell, J. (2008) Interactions between medial temporal lobe, prefrontal cortex, and inferior temporal regions during visual working memory: a combined intracranial EEG and functional magnetic resonance imaging study. J. Neurosci. 28(29): 7304-7312. Entrainment of electroencephalography (EEG) with transcranial alternating current stimulation Ryota Kanai, Institute of Cognitive Neuroscience, UCL, London, UK Brain activity measured with electroencephalography (EEG) on the scalp and intracranially recorded local field potentials exhibit oscillatory activities at various frequencies. Oscillatory activities at different frequencies from slow wave oscillations to high-gamma activities are thought to reflect different brain states and processing modes. However, their functional roles are yet to be determined. As an approach to investigate the roles of brain oscillations, we sought to use frequencyspecific brain stimulation to entrain oscillatory activity in the cortex. To do so, we employed transcranial alternating current stimulation (tACS) over the visual cortex and examined their influences on visual processing. We show that stimulating the brain with a biophysically relevant frequency can interact with ongoing EEG activity. More specifically, we show that stimulating the visual cortex with alternating current can induce perception of phosphenes in a frequency dependent manner. We compared the effects of delivering tACS under light and dark conditions. Stimulation over the occipital cortex induced perception of continuously flickering light most effectively when the beta (16Hz-24Hz) frequency range was applied in an illuminated room, whereas the most effective stimulation frequency shifted to the alpha frequency range when tested in darkness. This shift of the effective stimulation frequency mimics the shift of the dominant EEG frequency under the lighting conditions. Therefore, we inferred the frequency dependency is caused by interactions with ongoing oscillatory activity in the cortex stimulated (Kanai et al., 2008). One concern with this interpretation is that the source of phosphene induction may not be cortical but due to retinal stimulation (Schwiedrzik, 2009; Schutter in press). In order to test whether tACS over the visual cortex has an effect on the cortical activity rather than simply activating retinal neurons, we measured the cortical excitability of the visual cortex under tACS by measuring the thresholds of TMS-induced phosphenes. The experiment revealed that 20Hz tACS significantly increases the excitability of the visual cortex, whereas lower frequencies (4Hz and 10Hz) slightly reduced it. Our finding supports the idea that tACS indeed interacts with the ongoing EEG and modify the processing mode of the human cortex in a frequency dependent manner. Kanai, R., Chaieb, L., Antal, A., Walsh, V. & Paulus, W. (2008). Frequency-dependent electrical stimulation of the visual cortex. Curr Biol 18: 1839-43 Schwiedrzik, C.M. (2009). Retina or visual cortex? The site of phosphene induction by transcranial alternating current stimulation. Frontiers in Integrative Neuroscience, 3(6), 1-2. Slow wave sleep, EEG slow oscillations and the formation of memory Jan Born and Lisa Marshall, Department of Neuroendocrinology, University of Lübeck, Germany Slow-wave sleep (SWS) facilitates the consolidation of declarative memory (for facts, episodes) a process assumed to involve the redistribution of the memory representations from temporary hippocampal to neocortical long-term storage sites. Evidence will be provided indicating that this consolidation relies on a dialogue between neocortex and hippocampus which is essentially orchestrated by the <1 Hz EEG slow oscillation (SO). The SOs characterising SWS originate from neocortical networks. Their amplitude depends partly on the use of these networks for encoding of information, i.e., the more information is encoded during waking, the higher the SO amplitude during subsequent SWS. The SOs temporally group neuronal activity into up-states (of strongly enhanced activity) and down-states (of neuronal silence). This grouping is induced not only in the neocortex but also, via efferent pathways, in other structures relevant to consolidation, i.e., in the thalamus, generating 10-15 Hz spindles, and in the hippocampus, generating sharp-wave ripples which are wellknown to accompany a replay of newly encoded memories taking place in hippocampal circuitries during SWS. The feedforward synchronizing effect of the SO enables memory-related inputs to be synchronously fed back from these (hippocampus, thalamus) and other structures to the neocortex. The co-occurrence in the neocortex of these feedback-inputs possibly plays a critical role for the longterm storage of memories in neocortical networks. Indeed, induction of slow oscillations during NonREM sleep (but not during REM sleep or waking) by slowly alternating transcranial current stimulation not only enhances and synchronizes spindle activity but also improves the consolidation of declarative memory. Kirov, R., Weiss, C., Siebner, H.R., Born, J. and Marshall, L. (2009) Slow oscillation electrical brain stimulation during waking promotes EEG theta activity and memory encoding. Proc. Natl. Acad. Sci. 106(36): 15460-15465. Marshall, L., Helgadóttir, Mölle, M. and Born, J. (2006) Boosting slow oscillations during sleep potentiates memory. Nature 444(7119): 610-613. Marshall, L. and Born, J. (2007) The contribution of sleep to hippocampus-dependent memory formation. Trends Cogn. Sci. 11(10): 442-450. Weakly coupled oscillators Will Penny, Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London This talk presents an extension of the Dynamic Causal Modelling (DCM) framework to the analysis of phase-coupled data. A weakly coupled oscillator approach is used to describe dynamic phase changes in a network of oscillators. The use of Bayesian model comparison allows one to determine the mechanisms underlying synchronization processes in the brain. For example, whether activity is driven by master-slave versus mutual entrainment mechanisms. Results are presented on data from physiological models and on MEG data from a study of visual working memory. W Penny, V Litvak, L Fuentemilla, E Duzel, and K Friston. Dynamic Causal Models for Phase Coupling. J Neurosci Methods, 183(1):19-30, 2009. Ermentrout GB, Kleinfeld D. Traveling electrical waves in cortex: insights from phase dynamics and speculation on a computational role. Neuron. 2001 Jan;29(1):33-44. Dynamic Causal Models of Steady State responses: oscillatory connections Rosalyn Moran, Wellcome Trust Centre for Neuroimaging, Institute of Neurology, UCL, London, UK Cortico-basal ganglia-thalamocortical loop circuits are severely disrupted following dopamine depletion in Parkinson’s disease, leading to pathologically exaggerated beta oscillations in these networks. Their neural basis however, remains unclear. We used dynamic causal modelling and the 6hydroxydopamine-lesioned rat model of PD to examine the effective connectivity underlying these spectral abnormalities. We acquired measures of beta oscillations (10–35 Hz) from local field potential recordings of striatum, globus pallidus, subthalamic nucleus and cortex, and used these data to optimise neurobiologically-plausible models. Dopamine depletion led to a reorganisation of the basal ganglia-thalamocortical circuit with increased connectivity in the hyperdirect pathway and decreased connectivity from STN to GPe. A sensitivity analysis of the Parkinsonian circuit revealed that connectivity within the indirect pathway acquired a strategic importance that underpinned beta oscillations. These findings provide a radically new view of how connectivity in basal gangliathalamocortical circuits reflects pathogenic and compensatory processes, and predicts new therapeutic interventions. Simultaneous magnetoencephalography and subthalamic local field potential recordings in Parkinson patients Vladimir Litvak, UCL Institute of Neurology, London, UK Insight into how brain structures interact is critical for understanding the principles of brain function and may lead to better diagnosis and therapy. To study interactions between the cortex and deep brain structures (basal ganglia and the thalamus) we recorded, simultaneously, local field potentials (LFPs) from deep brain stimulation (DBS) electrodes and magnetoencephalographic (MEG) signals from the cerebral cortex (CTF 275 channel system) from Parkinson's disease (PD) patients with bilateral DBS electrodes in the subthalamic nucleus (STN). High-amplitude artefacts in the MEG, originating from slight movements of ferromagnetic parts of the electrode, pose a challenge to conventional analysis methods. However, we found that beamforming is capable of effectively suppressing these artefacts. We, therefore, used beamforming to obtain artefact-free source recordings from cortical areas whose activity is modulated by movement. Timefrequency analysis of the source data around finger movements revealed power dynamics consistent with previously published findings including event-related desynchronization followed by synchronization in the alpha and beta bands and high gamma activity around the time of movement in both motor cortex (M1) and STN. However, the effect of movement complexity on cortical and STN activity was not the same, indicating that the dynamics of M1 and STN are at least partially independent. We were also able to localize brain areas coherent with the STN-LFP signal and based on a large group of patients it seems that beta oscillations in the STN are specifically coherent with the ipsilateral premotor, superior frontal and inferior frontal areas. Brown P, Williams D (2005) Basal ganglia local field potential activity: character and functional significance in the human. Clin Neurophysiol 116:2510-2519. Cheyne D, Bells S, Ferrari P, Gaetz W, Bostan AC (2008) Self-paced movements induce high-frequency gamma oscillations in primary motor cortex. Neuroimage 42:332-342. Basal Ganglia activity in primate models of Parkinson’s disease. Léon Tremblay, CNRS, Centre de Neuroscience Cognitive, Lyon, France Parkinson’s disease (PD) has traditionally been considered as a neurological pathology characterized by a progressive, irreversible and ultimately disabling motor deficit. The motor symptoms (akinesia, rigidity and tremor) are also frequently associated with cognitive deficits that could appear in early stage of the disease. PD is related to dopamine (DA) depletion in the Basal Ganglia (BG), a consequence of degeneration of DA neurons localized in the substantia nigra pars compacta (SNc). About twenty years ago, the discovery of the neurotoxic effects of MPTP (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) on DA neurons provided an opportunity to study the physiopathology of PD in monkeys that expressed all the cardinal symptoms. Many studies have tried to characterize neuronal activities within the different BG structures and outside the BG at the thalamic and cortical level. Because they analyzed different parameters, these studies have reported a variety of changes: (1) changes of firing rate, (2) higher incidence of rhythmic and bursty firing patterns, (3) reduced specificity of responses to passive movements, and (4) excessive correlations between the discharges of distinct neurons. Two theoretical views may explain these different changes. According to DeLong (1990) the DA depletion could impair the balance between the direct and indirect pathways linking the striatum to the output structures (the internal segment of Globus pallidus (GPi) and the substantia nigra pars reticulata (SNr)). The high GPi/SNr firing rate may act as a brake on the pre-motor and motor cortex, via the inhibitory projection to the thalamus, resulting in akinesia. According to Bergman et al. (1998), the DA depletion could impair the functional segregation between striatopallidal pathways, resulting in both the loss of specificity and the excess of correlations. The inability to dissociate the BG output activities may lead to co-activations of antagonist motor programs resulting in both akinesia and rigidity. From these two hypotheses, the second one seems to explain better the neuronal dysfunctions observed inside the different studied structures in MPTP monkey model of PD. Moreover, the loss of selectivity to information that passes through the segregated functional circuits that link the different territories of BG (motor, associative and limbic) to the frontal cortex could also explain the cognitive deficits frequently observed in PD. The heterogeneity of the DA lesions and the compensatory mechanisms that appear gradually in the neuronal degenerative process, are two important characteristics that should be taken into account in the physiopathology of this disease. These two characteristics that we recently studied may partly explain the divergences of results previously observed. TREMBLAY, L., FILION, M. and BEDARD, P.J. (1989) Responses of pallidal neurons to striatal stimulation II. in monkeys with MPTP-induced parkinsonism. Brain Res., 498: 17-33. GUEHL, D., PESSIGLIONE, M., FRANCOIS, C., YELNIK, J. HIRSCH, E. C. FEGER, J. and TREMBLAY, L. (2003) Firing rate and pattern of neurons in "motor" thalamus during tremor in MPTP green monkeys model of Parkinsonism. European J. of Neuroscience : 17 : 2388-2400. PESSIGLIONE, M., GUEHL, D., ROLLAND, AS., FRANCOIS, C, HIRSCH, E. C. FEGER, J. and TREMBLAY, L. (2005) Thalamic neuronal activity in dopamine-depleted primates: Evidence for a loss of functional segragation within Basal Ganglia circuits. J Neuroscience 25(6):1523-1531. Effect of deep brain stimulation on the basal ganglia thalamocortical circuit Jerrold L Vitek MD, PhD, Dept of Neurosciences, Cleveland Clinic Foundation, USA Deep brain stimulation (DBS) in the subthalamic nucleus (STN) and the globus pallidus internus (GPi) elicits changes in the basal ganglia thalamocortical circuit that lead to marked improvement in the motor signs associated with Parkinson’s disease (PD) and dystonia. Although early hypotheses concerning the mechanism underlying this improvement focused on suppression of neuronal activity and a reduction of output from the stimulated structure, more recent work has suggested that DBS may exert its therapeutic effect via activation of output from the site of stimulation as well as fiber pathways passing through or lying adjacent to the site of stimulation. Data from multiple experimental formats including modeling, electrophysiological, microdialysis and imaging are consistent with the “activation hypothesis”. Activation of output from STN or GPi during DBS has been demonstrated to change the pattern, mean discharge rate, and degree of entropy as well as shift oscillatory frequencies in the basal ganglia thalamocortical circuit. How these changes lead to improvement in neurological symptoms has centered on the hypothesis that stimulation creates an informational lesion, i.e. information carried in the circuit is essentially uninformative, neither helpful or harmful. This concept has recently been challenged based on findings that DBS can improve signal processing in the motor cortex and via modeling/experimental studies suggesting that the fidelity of information transfer in thalamocortical circuits is improved during DBS. DBS may therefore exert its therapeutic effect, at least in part, by improving information processing and restoring function in subcortical-cortical and cortico-cortical networks. Hashimoto T, Elder CM, Okun MS, Patrick SK, and Vitek JL. Stimulation of the subthalamic nucleus changes the firing pattern of pallidal neurons. J Neurosci. 1:23)5): 1916-1923, 2003. Xu W, Russo G, Hashimoto T, Zhang J, Vitek JL. Subthalamic Nucleus stimulation modulates thalamic neuronal activity. J. Neurosci. PMID : 19005057, 28 :11916-11924, 2008. Guo Y, Rubin JE, McIntyre CC, Vitek JL, Terman D. Thalamocortical relay fidelity varies across subthalamic nucleus deep brain stimulation protocols in a data-driven computational model. J. Neurophsiol. PMID: 18171706, March 99(3): 1477-92, 2008. Dorval AD, Russo GS, Hashimoto T, Xu W, Grill WM, Vitek JL. Deep Brain Stimulation reduces neuronal entropy in the MPTP-Primate model of Parkinson’s disease. J. Neurophysiol. 100:2807-2818, 2008. Johnson MD, Vitek JL, McIntyre CC. Pallidal stimulation that improves parkinsonian motor symptoms also modulates neuronal firing patterns in primary motor cortex in the MPTP-treated monkey. Experimental Neurology, 209(1):259-62, 2009. Developing brain machine interfaces for deep brain stimulation Tim Denison, Medtronic Neuromdulation Technology, Minneapolis, USA This talk discusses designing technology for brain-machine interfaces (BMI). Advances in BMI technology might potentially help improve devices treating neurological conditions. Designing a BMI system is a complex engineering problem drawing on such diverse fields as applied physics, circuit design, algorithms and biology. Fundamental to device design is the neurophysiology of the 'brain circuits' and how a circuit designer chooses to interface with these networks. To put these concepts in context, we describe recent work in prototyping bi-directional BMIs that seek to provide adaptive neuromodulation of a neural circuit based on detected electrical biomarkers in the brain, particularly oscillations in the field potentials of key neural circuits. This application highlights how advancements in merging silicon and biological systems, reflected in BMI design, seeks to help advance the treatment of a variety of neurological disorders. Csavoy, Andrew; Molnar, Gregory; Denison, Timothy, "Creating support circuits for the nervous system: Considerations for "brain-machine" interfacing," VLSI Circuits, 2009 Symposium on , vol., no., pp.4-7, 16-18 June 2009 Avestruz, A.-T.; Santa, W.; Carlson, D.; Jensen, R.; Stanslaski, S.; Helfenstine, A.; Denison, T., "A 5 micro W/Channel Spectral Analysis IC for Chronic Bidirectional Brain-Machine Interfaces," Solid-State Circuits, IEEE Journal of , vol.43, no.12, pp.3006-3024, Dec. 2008