Paired Associative Stimulation Rewired: A Novel Paradigm to Modulate Resting-State Intracortical Connectivity

Recent neuroimaging research has demonstrated that resting-state intracortical connectivity (i.e., the shared communication between two brain regions) can serve as a robust predictor of motor performance and learning. Theoretically, direct modulation of resting-state intracortical connectivity within the motor system could then improve motor performance and learning. However, previous neuromodulation techniques such as repetitive Transcranial Magnetic Stimulation may be limited in the capacity to modulate targeted intracortical connectivity. Paired Associative Stimulation (PAS) has shown efficacy in facilitating connectivity primarily between the central and peripheral nervous system based on the neuroplasticity mechanism of Spike Timing Dependent Plasticity. It may therefore be plausible for a reconfigured corticocortical PAS paradigm to modulate resting-state intracortical connectivity using a dual stimulator methodology over specific cortical nodes. However, potential theoretical and technological considerations of such a paradigm first need to be addressed prior to application for the purposes of manipulating motor behavior. We posit a corticocortical PAS paradigm used in conjunction with resting-state electroencephalography to demonstrate efficacy of potentiating motor learning associated resting-state intracortical connectivity within the human brain. Here we provide a precise PAS/EEG experimental design, details on data analysis, recommendations for maintaining scientific rigor, and preliminary proof of principle within a single-subject.

Propagation of cortical activity via open-loop intrathalamic architectures: a computational analysis

Propagation of signals across the cerebral cortex is a core component of many cognitive processes and is generally thought to be mediated by direct intracortical connectivity. The thalamus, by contrast, is considered to be devoid of internal connections and organized as a collection of parallel inputs to the cortex. Here, we provide evidence that “open-loop” intrathalamic connections involving the thalamic reticular nucleus (TRN) can support propagation of oscillatory activity across the cortex. Recent studies support the existence of open-loop thalamo-reticulo-thalamic (TC-TRN-TC) synaptic motifs in addition to traditional closed-loop architectures. We hypothesized that open-loop structural modules, when connected in series, might underlie thalamic and, therefore cortical, signal propagation. Using a supercomputing platform to simulate thousands of permutations of a thalamo-reticular-cortical network and allowing select synapses to vary both by class and individually, we evaluated the relative capacities of closed- and open-loop TC-TRN-TC synaptic configurations to support both propagation and oscillation. We observed that 1) signal propagation was best supported in networks possessing strong open-loop TC-TRN-TC connectivity; 2) intrareticular synapses were neither primary substrates of propagation nor oscillation; and 3) heterogeneous synaptic networks supported more robust propagation of oscillation than their homogeneous counterparts. These findings suggest that open-loop heterogeneous intrathalamic architectures complement direct intracortical connectivity to facilitate cortical signal propagation.Significance StatementInteractions between the dorsal thalamus and thalamic reticular nucleus (TRN) are speculated to contribute to phenomena such as arousal, attention, sleep, and seizures. Despite the importance of the TRN, the synaptic microarchitectures forming the basis for dorsal thalamus-TRN interactions are not fully understood. The computational neural model we present incorporates “open-loop” thalamo-reticular-thalamic (TC-TRN-TC) synaptic motifs, which have been experimentally observed. We elucidate how open-loop motifs possess the capacity to shape the propagative properties of signals intrinsic to the thalamus and evaluate the wave dynamics they support relative to closed-loop TC-TRN-TC pathways and intrareticular synaptic connections. Our model also generates predictions regarding how different spatial distributions of reticulothalamic and intrareticular synapses affect these signaling properties.

Temporal Symmetry in Primary Auditory Cortex: Implications for Cortical Connectivity

Neurons in primary auditory cortex (AI) in the ferret (Mustela putorius) that are well described by their spectrotemporal response field (STRF) are found also to have a distinctive property that we call temporal symmetry. For temporally symmetric neurons, every temporal cross-section of the STRF (impulse response) is given by the same function of time, except for a scaling and a Hilbert rotation. This property held in 85% of neurons (123 out of 145) recorded from awake animals and in 96% of neurons (70 out of 73) recorded from anesthetized animals. This property of temporal symmetry is highly constraining for possible models of functional neural connectivity within and into AI. We find that the simplest models of functional thalamic input, from the ventral medial geniculate body (MGB), into the entry layers of AI are ruled out because they are incompatible with the constraints of the observed temporal symmetry. This is also the case for the simplest models of functional intracortical connectivity. Plausible models that do generate temporal symmetry, from both thalamic and intracortical inputs, are presented. In particular, we propose that two specific characteristics of the thalamocortical interface may be responsible. The first is a temporal mismatch between the fast dynamics of the thalamus and the slow responses of the cortex. The second is that all thalamic inputs into a cortical module (or a cluster of cells) must be restricted to one point of entry (or one cell in the cluster). This latter property implies a lack of correlated horizontal interactions across cortical modules during the STRF measurements. The implications of these insights in the auditory system, and comparisons with similar properties in the visual system, are explored.