Large-scale Spatiotemporal Spike Patterning Consistent with Wave Propagation in Motor Cortex

Aggregate signals in cortex are known to be spatiotemporally organized as propagating waves across the cortical surface, but it remains unclear whether the same is true for spiking activity in individual neurons. Furthermore, the functional interactions between cortical neurons are well documented but their spatial arrangement on the cortical surface has been largely ignored. Here we use a functional network analysis to demonstrate that a subset of motor cortical neurons in non-human primates spatially coordinate their spiking activity in a manner that closely matches wave propagation measured in the beta oscillatory band of the local field potential. We also demonstrate that sequential spiking of pairs of neuron contains task-relevant information that peaks when the neurons are spatially oriented along the wave axis. We hypothesize that the spatial anisotropy of spike patterning may reflect the underlying organization of motor cortex and may be a general property shared by other cortical areas

Aberrant activity in conceptual networks underlies N400 deficits and unusual thoughts in schizophrenia.

BackgroundThe N400 event-related potential (ERP) is triggered by meaningful stimuli that are incongruous, or unmatched, with their semantic context. Functional magnetic resonance imaging (fMRI) studies have identified brain regions activated by semantic incongruity, but their precise links to the N400 ERP are unclear. In schizophrenia (SZ), N400 amplitude reduction is thought to reflect overly broad associations in semantic networks, but the abnormalities in brain networks underlying deficient N400 remain unknown. We utilized joint independent component analysis (JICA) to link temporal patterns in ERPs to neuroanatomical patterns from fMRI and investigate relationships between N400 amplitude and neuroanatomical activation in SZ patients and healthy controls (HC).MethodsSZ patients (n = 24) and HC participants (n = 25) performed a picture-word matching task, in which words were either matched (APPLE→apple) by preceding pictures, or were unmatched by semantically related (in-category; IC, APPLE→lemon) or unrelated (out of category; OC, APPLE→cow) pictures, in separate ERP and fMRI sessions. A JICA "data fusion" analysis was conducted to identify the fMRI brain regions specifically associated with the ERP N400 component. SZ and HC loading weights were compared and correlations with clinical symptoms were assessed.ResultsJICA identified an ERP-fMRI "fused" component that captured the N400, with loading weights that were reduced in SZ. The JICA map for the IC condition showed peaks of activation in the cingulate, precuneus, bilateral temporal poles and cerebellum, whereas the JICA map from the OC condition was linked primarily to visual cortical activation and the left temporal pole. Among SZ patients, fMRI activity from the IC condition was inversely correlated with unusual thought content.ConclusionsThe neural networks associated with the N400 ERP response to semantic violations depends on conceptual relatedness. These findings are consistent with a distributed network underlying neural responses to semantic incongruity including unimodal visual areas as well as integrative, transmodal areas. Unusual thoughts in SZ may reflect impaired processing in transmodal hub regions such as the precuneus, leading to overly broad semantic associations

Default activity patterns at the neocortical microcircuit level

Even in absence of sensory stimuli cortical networks exhibit complex, self-organized activity patterns. While the function of those spontaneous patterns of activation remains poorly understood, recent studies both in vivo and in vitro have demonstrated that neocortical neurons activate in a surprisingly similar sequential order both spontaneously and following input into cortex. For example, neurons that tend to fire earlier within spontaneous bursts of activity also fire earlier than other neurons in response to sensory stimuli. These “default patterns” can last hundreds of milliseconds and are strongly conserved under a variety of conditions. In this paper, we will review recent evidence for these default patterns at the local cortical level. We speculate that cortical architecture imposes common constraints on spontaneous and evoked activity flow, which result in the similarity of the patterns

Simultaneous mesoscopic and two-photon imaging of neuronal activity in cortical circuits.

Spontaneous and sensory-evoked activity propagates across varying spatial scales in the mammalian cortex, but technical challenges have limited conceptual links between the function of local neuronal circuits and brain-wide network dynamics. We present a method for simultaneous cellular-resolution two-photon calcium imaging of a local microcircuit and mesoscopic widefield calcium imaging of the entire cortical mantle in awake mice. Our multi-scale approach involves a microscope with an orthogonal axis design where the mesoscopic objective is oriented above the brain and the two-photon objective is oriented horizontally, with imaging performed through a microprism. We also introduce a viral transduction method for robust and widespread gene delivery in the mouse brain. These approaches allow us to identify the behavioral state-dependent functional connectivity of pyramidal neurons and vasoactive intestinal peptide-expressing interneurons with long-range cortical networks. Our imaging system provides a powerful strategy for investigating cortical architecture across a wide range of spatial scales

Global neural rhythm control by local neuromodulation

Neural oscillations are a ubiquitous form of neural activity seen across scales and modalities. These neural rhythms correlate with diverse cognitive functions and brain states. One mechanism for changing the oscillatory dynamics of large neuronal populations is through neuromodulator activity. An intriguing phenomenon explored here is when local neuromodulation of a distinct neuron type within a single brain nucleus exerts a powerful influence on global cortical rhythms. One approach to investigate the impact of local circuits on global rhythms is through optogenetic techniques. My first project involves the statistical analysis of electrophysiological recordings of an optogenetically-mediated Parkinsonian phenotype. Empirical studies demonstrate that Parkinsonian motor deficits correlate with the emergence of exaggerated beta frequency (15-30 Hz) oscillations throughout the cortico-basal ganglia-thalamic network. However, the mechanism of these aberrant oscillatory dynamics is not well understood. A previous modeling study predicted that cholinergic neuromodulation of medium spiny neurons in the striatum of the basal ganglia may mediate the pathologic beta rhythm. Here, this hypothesis was tested using selective optogenetic stimulation of striatal cholinergic interneurons in normal mice; stimulation robustly and reversibly amplified beta oscillations and Parkinsonian motor symptoms. The modulation of global rhythms by local networks was further studied using computational modeling in the context of intrathalamic neuromodulation. While intrathalamic vasoactive intestinal peptide (VIP) is known to cause long-lasting excitation in vitro, its in vivo dynamical effects have not been reported. Here, biophysical computational models were used to elucidate the impact of VIP on thalamocortical dynamics during sleep and propofol general anesthesia. The modeling results suggest that VIP can form robust sleep spindle oscillations and control aspects of sleep architecture through a novel homeostatic mechanism. This homeostatic mechanism would be inhibited by general anesthesia, representing a new mechanism contributing to anesthetic-induced loss of consciousness. While the previous two projects differed in their use of empirical versus theoretical methods, a challenge common to both domains is the difficulty in visualizing and analyzing large multi-dimensional datasets. A tool to mitigate these issues is introduced here: GIMBL-Vis is a Graphical Interactive Multi-dimensional extensiBLe Visualization toolbox for Matlab. This toolbox simplifies the process of exploring multi-dimensional data in Matlab by providing a graphical interface for visualization and analysis. Furthermore, it provides an extensible open platform for distributed development by the community

Modulation of I-wave generating pathways by TBS: a model of plasticity induction

KEY POINTS: • Mechanisms underlying plasticity induction by repetitive transcranial magnetic stimulation protocols such as intermittent theta-burst stimulation (iTBS) remain poorly understood. • Individual response to iTBS is associated with recruitment of late indirect wave (I-wave) generating pathways that can be probed by the onset latency of TMS applied to primary motor cortex (M1) at different coil orientations. • We found an association between late I-wave recruitment (reflected by AP-LM latency, i.e. the excess latency of motor evoked potentials (MEPs) generated by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation) and changes in cortical excitability following iTBS, confirming previous studies. •AP-LM latency significantly decreased following iTBS, and this decrease correlated with the iTBS-induced increase in cortical excitability across subjects. •Plasticity in the motor network may in part derive from a modulation of excitability and recruitment of late I-wave generating cortical pathways. ABSTRACT: Plasticity-induction following theta burst transcranial stimulation (TBS) varies considerably across subjects, and underlying neurophysiological mechanisms remain poorly understood, representing a challenge for scientific and clinical applications. In human motor cortex (M1), recruitment of indirect waves (I-waves) can be probed by the excess latency of motor evoked potentials (MEPs) elicited by TMS with an anterior-posterior (AP) orientation over the latency of MEPs evoked by direct activation of corticospinal axons using latero-medial (LM) stimulation, referred to as "AP-LM latency" difference. Importantly, AP-LM latency has been shown to predict individual responses to TBS across subjects. We, therefore, hypothesized that the plastic changes in corticospinal excitability induced by TBS are the result, at least in part, of changes in excitability of these same I-wave generating pathways. We investigated in 20 healthy subjects whether intermittent TBS (iTBS) modulates I-wave recruitment as reflected by changes in the AP-LM latency. As expected, we found that AP-LM latencies before iTBS were associated with iTBS-induced excitability changes. A novel finding was that iTBS reduced the AP-LM latency, and that this correlated significantly with changes in cortical excitability observed following iTBS: subjects with the largest reductions in AP-LM latencies had the largest increases in cortical excitability following iTBS. Our findings suggest that plasticity-induction by iTBS may derive from the modulation of I-wave generating pathways projecting onto M1, accounting for the predictive potential of I-wave recruitment. The excitability of I-wave generating may serve a critical role in modulating motor cortical excitability and hence represent a promising target for novel rTMS protocols

Physiological sharp wave-ripples and interictal events in vitro: What’s the difference?

Sharp wave-ripples and interictal events are physiological and pathological forms of transient high activity in the hippocampus with similar features. Sharp wave-ripples have been shown to be essential in memory consolidation, while epileptiform (interictal) events are thought to be damaging. It is essential to grasp the difference between physiological sharp wave-ripples and pathological interictal events in order to understand the failure of control mechanisms in the latter case. We investigated the dynamics of activity generated intrinsically in the CA3 region of the mouse hippocampus in vitro, using four different types of intervention to induce epiletiform activity. As a result, sharp wave-ripples spontaneously occurring in CA3 disappeared, and following an asynchronous transitory phase, activity reorganized into a new form of pathological synchrony. During epileptiform events, all neurons increased their firing rate compared to sharp wave-ripples. Different cell types showed complementary firing: parvalbumin-positive basket cells and some axo-axonic cells stopped firing due to a depolarization block at the climax of the events in high potassium, 4-aminopyridine and zero magnesium models, but not in the gabazine model. In contrast, pyramidal cells started firing maximally at this stage. To understand the underlying mechanism we measured changes of intrinsic neuronal and transmission parameters in the high potassium model. We found that the cellular excitability increased and excitatory transmission was enhanced, whereas inhibitory transmission was compromised. We observed a strong short-term depression in parvalbumin-positive basket cell to pyramidal cell transmission. Thus, the collapse of pyramidal cell perisomatic inhibition appears to be a crucial factor in the emergence of epileptiform events