A perspective on cortical layering and layer-spanning neuronal elements

This review article addresses the function of the layers of the cerebral cortex. We develop the perspective that cortical layering needs to be understood in terms of its functional anatomy, i.e., the terminations of synaptic inputs on distinct cellular compartments and their effect on cortical activity. The cortex is a hierarchical structure in which feed forward and feedback pathways have a layer-specific termination pattern. We take the view that the influence of synaptic inputs arriving at different cortical layers can only be understood in terms of their complex interaction with cellular biophysics and the subsequent computation that occurs at the cellular level. We use high-resolution fMRI, which can resolve activity across layers, as a case study for implementing this approach by describing how cognitive events arising from the laminar distribution of inputs can be interpreted by taking into account the properties of neurons that span different layers. This perspective is based on recent advances in measuring subcellular activity in distinct feed-forward and feedback axons and in dendrites as they span across layers

IFCN-endorsed practical guidelines for clinical magnetoencephalography (MEG)

Magnetoencephalography (MEG) records weak magnetic fields outside the human head and thereby provides millisecond-accurate information about neuronal currents supporting human brain function. MEG and electroencephalography (EEG) are closely related complementary methods and should be interpreted together whenever possible. This manuscript covers the basic physical and physiological principles of MEG and discusses the main aspects of state-of-the-art MEG data analysis. We provide guidelines for best practices of patient preparation, stimulus presentation, MEG data collection and analysis, as well as for MEG interpretation in routine clinical examinations. In 2017, about 200 whole-scalp MEG devices were in operation worldwide, many of them located in clinical environments. Yet, the established clinical indications for MEG examinations remain few, mainly restricted to the diagnostics of epilepsy and to preoperative functional evaluation of neurosurgical patients. We are confident that the extensive ongoing basic MEG research indicates potential for the evaluation of neurological and psychiatric syndromes, developmental disorders, and the integrity of cortical brain networks after stroke. Basic and clinical research is, thus, paving way for new clinical applications to be identified by an increasing number of practitioners of MEG. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.Peer reviewe

Recovery of cortical effective connectivity and recovery of consciousness in vegetative patients

Patients surviving severe brain injury may regain consciousness without recovering their ability to understand, move and communicate. Recently, electrophysiological and neuroimaging approaches, employing simple sensory stimulations or verbal commands, have proven useful in detecting higher order processing and, in some cases, in establishing some degree of communication in brain-injured subjects with severe impairment of motor function. To complement these approaches, it would be useful to develop methods to detect recovery of consciousness in ways that do not depend on the integrity of sensory pathways or on the subject's ability to comprehend or carry out instructions. As suggested by theoretical and experimental work, a key requirement for consciousness is that multiple, specialized cortical areas can engage in rapid causal interactions (effective connectivity). Here, we employ transcranial magnetic stimulation together with high-density electroencephalography to evaluate effective connectivity at the bedside of severely brain injured, non-communicating subjects. In patients in a vegetative state, who were open-eyed, behaviourally awake but unresponsive, transcranial magnetic stimulation triggered a simple, local response indicating a breakdown of effective connectivity, similar to the one previously observed in unconscious sleeping or anaesthetized subjects. In contrast, in minimally conscious patients, who showed fluctuating signs of non-reflexive behaviour, transcranial magnetic stimulation invariably triggered complex activations that sequentially involved distant cortical areas ipsi- and contralateral to the site of stimulation, similar to activations we recorded in locked-in, conscious patients. Longitudinal measurements performed in patients who gradually recovered consciousness revealed that this clear-cut change in effective connectivity could occur at an early stage, before reliable communication was established with the subject and before the spontaneous electroencephalogram showed significant modifications. Measurements of effective connectivity by means of transcranial magnetic stimulation combined with electroencephalography can be performed at the bedside while by-passing subcortical afferent and efferent pathways, and without requiring active participation of subjects or language comprehension; hence, they offer an effective way to detect and track recovery of consciousness in brain-injured patients who are unable to exchange information with the external environment

The multisensory function of the human primary visual cortex

It has been nearly 10 years since Ghazanfar and Schroeder (2006) proposed that the neocortex is essentially multisensory in nature. However, it is only recently that sufficient and hard evidence that supports this proposal has accrued. We review evidence that activity within the human primary visual cortex plays an active role in multisensory processes and directly impacts behavioural outcome. This evidence emerges from a full pallet of human brain imaging and brain mapping methods with which multisensory processes are quantitatively assessed by taking advantage of particular strengths of each technique as well as advances in signal analyses. Several general conclusions about multisensory processes in primary visual cortex of humans are supported relatively solidly. First, haemodynamic methods (fMRI/PET) show that there is both convergence and integration occurring within primary visual cortex. Second, primary visual cortex is involved in multisensory processes during early post-stimulus stages (as revealed by EEG/ERP/ERFs as well as TMS). Third, multisensory effects in primary visual cortex directly impact behaviour and perception, as revealed by correlational (EEG/ERPs/ERFs) as well as more causal measures (TMS/tACS). While the provocative claim of Ghazanfar and Schroeder (2006) that the whole of neocortex is multisensory in function has yet to be demonstrated, this can now be considered established in the case of the human primary visual cortex

Refinement of neuronal synchronization with gamma oscillations in the medial prefrontal cortex after adolescence

The marked anatomical and functional changes taking place in the medial prefrontal cortex (PFC) during adolescence set grounds for the high incidence of neuropsychiatric disorders with adolescent onset. Although circuit refinement through synapse pruning may constitute the anatomical basis for the cognitive differences reported between adolescents and adults, a physiological correlate of circuit refinement at the level of neuronal ensembles has not been demonstrated. We have recorded neuronal activity together with local field potentials in the medial PFC of juvenile and adult mice under anesthesia, which allowed studying local functional connectivity without behavioral or sensorial interference. Entrainment of pyramidal neurons and interneurons to gamma oscillations, but not to theta or beta oscillations, was reduced after adolescence. Interneurons were synchronized to gamma oscillations across a wider area of the PFC than pyramidal neurons, and the span of interneuron synchronization was shorter in adults than juvenile mice. Thus, transition from childhood to adulthood is characterized by reduction of the strength and span of neuronal synchronization specific to gamma oscillations in the mPFC. The more restricted and weak ongoing synchronization in adults may allow a more dynamic rearrangement of neuronal ensembles during behavior and promote parallel processing of information.Fil: de Almeida, Julián. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Jourdan, Iván. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Universidad de Buenos Aires. Facultad de Ingeniería; ArgentinaFil: Murer, Mario Gustavo. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Belforte, Juan Emilio. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Ciencias Fisiológicas. Laboratorio de Fisiología de Circuitos Neuronales; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

The interplay between long- and short-range temporal correlations shapes cortex dynamics across vigilance states

Increasing evidence suggests that cortical dynamics during wake exhibits long-range temporal correlations suitable to integrate inputs over extended periods of time to increase the signal-to-noise ratio in decision-making and working memory tasks. Accordingly, sleep has been suggested as a state characterized by a breakdown of long-range correlations; detailed measurements of neuronal timescales that support this view, however, have so far been lacking. Here we show that the long timescales measured at the individual neuron level in freely-behaving rats during the awake state are abrogated during non-REM (NREM) sleep. We provide evidence for the existence of two distinct states in terms of timescale dynamics in cortex: one which is characterized by long timescales which dominate during wake and REM sleep, and a second one characterized by the absence of long-range temporal correlations which characterizes NREM sleep. We observe that both timescale regimes can co-exist and, in combination, lead to an apparent gradual decline of long timescales during extended wake which is restored after sleep. Our results provide a missing link between the observed long timescales in individual neuron fluctuations during wake and the reported absence of long-term correlations during deep sleep in EEG and fMRI studies. They furthermore suggest a network-level function of sleep, to reorganize cortical networks towards states governed by slow cortex dynamics to ensure optimal function for the time awake

Characterising mismatch negativity biomarker signatures in preclinical models relevant to schizophrenia

Mismatch negativity (MMN) has been hailed as a "break-through biomarker in predicting psychosis onset" (Naatanen 2015). This is because deficits have been found in clinical populations diagnosed with psychotic syndromes such as schizophrenia. MMN is an auditory evoked potential (AEP) difference waveform produced by subtracting standard from deviant stimuli AEPs elicited by an oddball paradigm; purportedly arising from any discriminable change in auditory stimulation.;Despite nearly four decades of basic research into MMN the underlying mechanisms are not fully understood. Although popular theories suggest that it reflects a sensory-memory trace disruption and/or differential adaptation of responses to standard and deviant/oddball stimuli, there remains considerable debate over the neural mechanism and its interpretation.;Nevertheless, associations made between N-methyl-d-aspartate (NMDA) receptors in schizophrenia and findings showing that NMDA receptor antagonists (e.g. ketamine) induce MMN deficits in healthy volunteers suggests abnormal MMNs share common traits and support its use as a biomarker from an electrophysiological perspective. However, this is still speculative and there is great impetus on developing reliable preclinical models of MMN in order to examine the underpinning neurophysiology and therefore its reliance on NMDA receptors as a test of pathology in schizophrenia.;A question this thesis aims to address is whether a mismatch response (MMR) exists in rodents which is analogous to the human MMN, and whether its modification by NMDA receptor antagonists or as a result of schizophrenia-related genetic modification sheds light on its utility as a biomarker in disease models of schizophrenia.;This thesis describes three experiments performed using mitogen activated protein kinase kinase 7 heterozygous (Map2k7+/−) mice and their wild-type littermates, incorporating NMDA receptor antagonism with ketamine (10 mg/kg i.p.). The MAP2K7 gene is associated with schizophrenia and codes for a post-synaptic intracellular signalling enzyme which is activated following glutamatergic excitation, for instance via NMDA receptors.;The MMR to stimuli duration, frequency and intensity changes in oddball paradigms are characterised in urethane-anaesthetised and conscious animals, followed by an examination of laminar auditory cortex activity in response to these physical changes. Data recorded throughout this series of experiments includes cortical electroencephalography (EEG), video footage, and intra-cortical spiking information. These data were then analysed using various time, frequency and time-frequency domain techniques; although mainly focussing on the event-related potential (ERP) approach.;Recordings demonstrated substantial differences in the AEP waveform evoked from urethane-anaesthetised and conscious animals, with the latter displaying considerably more dynamic responses, although onset and offset of auditory stimuli induced comparable waveform features in both states. Effects of varying physical properties of stimuli in oddball and control paradigms have been identified as key determinants of the AEP and correspondingly the MMR difference waveform amplitudes.;The finding that NMDA receptor disruption in conscious animals by ketamine acutely diminishes a specific AEP feature (≈20-50 ms post stimulus onset) which may impact the resulting MMR tentatively links this study in mice with findings from humans noted above. Ketamine was also found to enhance animal movement and increase EEG spectral power in the 50-70 Hz (gamma-band) frequency range, observed for approximately 10 minutes following drug administration.;Both anaesthetised and conscious cohorts of Map2k7+/− mice displayed a significantly enhanced onset response (≈0-20 ms) in the AEP. Interestingly, ketamine did not appear to have a differential effect on Map2k7+/− mice compared with the wild-type group, suggesting that NMDA receptor-mediated neurotransmission is unimpaired in this genetic model relevant to schizophrenia.;Overall, the findings suggest that the MMR in mice is fundamentally influenced by the physical properties of stimuli employed; ketamine causes an acute, specific alteration to the AEP in conscious mice in addition to other electrophysiological and behavioural changes; and Map2k7 gene disruption causes a specific and replicable change in AEP amplitude.;Overall this study indicates that mouse models are useful for exploring the effects of different pharmacological and genetic manipulations on the auditory evoked response; however, MMN data in clinical cohorts still needs to be interpreted with care. In order to address whether the rodent MMR is analogous to human MMN, it would be necessary to probe how influencing factors revealed in the rodent studies impact on the human response. Whilst the rodent MMR and human MMN show some degree of translation, their potential as schizophrenia biomarkers requires further characterisation and validation.Mismatch negativity (MMN) has been hailed as a "break-through biomarker in predicting psychosis onset" (Naatanen 2015). This is because deficits have been found in clinical populations diagnosed with psychotic syndromes such as schizophrenia. MMN is an auditory evoked potential (AEP) difference waveform produced by subtracting standard from deviant stimuli AEPs elicited by an oddball paradigm; purportedly arising from any discriminable change in auditory stimulation.;Despite nearly four decades of basic research into MMN the underlying mechanisms are not fully understood. Although popular theories suggest that it reflects a sensory-memory trace disruption and/or differential adaptation of responses to standard and deviant/oddball stimuli, there remains considerable debate over the neural mechanism and its interpretation.;Nevertheless, associations made between N-methyl-d-aspartate (NMDA) receptors in schizophrenia and findings showing that NMDA receptor antagonists (e.g. ketamine) induce MMN deficits in healthy volunteers suggests abnormal MMNs share common traits and support its use as a biomarker from an electrophysiological perspective. However, this is still speculative and there is great impetus on developing reliable preclinical models of MMN in order to examine the underpinning neurophysiology and therefore its reliance on NMDA receptors as a test of pathology in schizophrenia.;A question this thesis aims to address is whether a mismatch response (MMR) exists in rodents which is analogous to the human MMN, and whether its modification by NMDA receptor antagonists or as a result of schizophrenia-related genetic modification sheds light on its utility as a biomarker in disease models of schizophrenia.;This thesis describes three experiments performed using mitogen activated protein kinase kinase 7 heterozygous (Map2k7+/−) mice and their wild-type littermates, incorporating NMDA receptor antagonism with ketamine (10 mg/kg i.p.). The MAP2K7 gene is associated with schizophrenia and codes for a post-synaptic intracellular signalling enzyme which is activated following glutamatergic excitation, for instance via NMDA receptors.;The MMR to stimuli duration, frequency and intensity changes in oddball paradigms are characterised in urethane-anaesthetised and conscious animals, followed by an examination of laminar auditory cortex activity in response to these physical changes. Data recorded throughout this series of experiments includes cortical electroencephalography (EEG), video footage, and intra-cortical spiking information. These data were then analysed using various time, frequency and time-frequency domain techniques; although mainly focussing on the event-related potential (ERP) approach.;Recordings demonstrated substantial differences in the AEP waveform evoked from urethane-anaesthetised and conscious animals, with the latter displaying considerably more dynamic responses, although onset and offset of auditory stimuli induced comparable waveform features in both states. Effects of varying physical properties of stimuli in oddball and control paradigms have been identified as key determinants of the AEP and correspondingly the MMR difference waveform amplitudes.;The finding that NMDA receptor disruption in conscious animals by ketamine acutely diminishes a specific AEP feature (≈20-50 ms post stimulus onset) which may impact the resulting MMR tentatively links this study in mice with findings from humans noted above. Ketamine was also found to enhance animal movement and increase EEG spectral power in the 50-70 Hz (gamma-band) frequency range, observed for approximately 10 minutes following drug administration.;Both anaesthetised and conscious cohorts of Map2k7+/− mice displayed a significantly enhanced onset response (≈0-20 ms) in the AEP. Interestingly, ketamine did not appear to have a differential effect on Map2k7+/− mice compared with the wild-type group, suggesting that NMDA receptor-mediated neurotransmission is unimpaired in this genetic model relevant to schizophrenia.;Overall, the findings suggest that the MMR in mice is fundamentally influenced by the physical properties of stimuli employed; ketamine causes an acute, specific alteration to the AEP in conscious mice in addition to other electrophysiological and behavioural changes; and Map2k7 gene disruption causes a specific and replicable change in AEP amplitude.;Overall this study indicates that mouse models are useful for exploring the effects of different pharmacological and genetic manipulations on the auditory evoked response; however, MMN data in clinical cohorts still needs to be interpreted with care. In order to address whether the rodent MMR is analogous to human MMN, it would be necessary to probe how influencing factors revealed in the rodent studies impact on the human response. Whilst the rodent MMR and human MMN show some degree of translation, their potential as schizophrenia biomarkers requires further characterisation and validation

Clozapine-induced paroxysmal discharges

PhD ThesisThe atypical antipsychotic clozapine is a widely prescribed and effective treatment for the positive and negative symptoms of schizophrenia, but reports of side effects are common. In one study EEG abnormalities were observed in 53% of patients treated with clozapine, and the absence or presence of EEG abnormalities correlated with the plasma clozapine concentration. Here, epileptiform activity was present in conventional EEG recordings from a 32 year old male patient with psychiatric illness taking clozapine for 3 weeks. Brief (ca.100ms), transient epileptiform spikes occurred at a frequency of approximately 2 per h and originated primarily in parietal cortex. One month after withdrawal of clozapine, epileptiform spikes were no longer present. An in vitro model was developed using the equivalent region of association cortex, namely 2⁰ somatosensory cortex, in normal rat brain slices to probe such activity with increased spatial and temporal resolution, and to investigate mechanisms underlying its generation. Wide band in vitro recordings revealed that clozapine (10-20µM) induced regular, frequent very fast oscillations (VFO, > 70Hz) in this region. These VFO comprised short transient high frequency discharges and were maximal in patches along layer V. The atypical antipsychotic olanzapine, but not the classical antipsychotic haloperidol, also induced prominent VFO in this region. Sharp electrode intracellular recordings revealed that there was almost no correlation between the somatic activity of layer V regular spiking (RS) pyramidal cells and field VFO, but layer V intrinsically bursting (IB) cells did correlate to some extent with the local field. Interestingly, IB cell spikelets were also weakly correlated with field VFO suggesting a role for axonal hyperexcitability in this cell type in the mechanism. Clozapine-induced VFO persisted following blockade of AMPA, NMDA, and GABAA chemical synaptic receptors, and the gap junction blockers carbenoxolone and quinine also failed to significantly attenuate the power of this activity. Although octanol abolished clozapine-induced VFO, it was not clear that this effect resulted from blockade of gap junctions as this drug also blocks spikes. In addition to VFO events, clozapine (10-20µM) also induced occasional, spontaneous transient paroxysmal discharges, similar to the EEG phenomena, in 33% (11/33 slices) of slices in vitro. Sharp electrode intracellular recordings revealed that clozapine- induced full paroxysmal discharges were associated with spikes, EPSPs and IPSPs in layer V RS and IB cells, suggesting that these events were mediated via chemical synaptic transmission in both of these cell types. Multi-electrode array recordings of local field potentials and units suggested that clozapine-induced paroxysmal events started superficially in association cortex, moved deeper and then propagated horizontally along these deep layers. The onset of clozapine-induced VFO was accompanied by a significant elevation in parvalbumin immunoreactivity, particularly in layer II-IV, where there was a greater than twofold increase in the signal, and this may be relevant to the therapeutic action of the drug