Inferring connection proximity in networks of electrically coupled cells by subthreshold frequency response analysis

Electrical synapses continuously transfer signals bi-directionally from one cell to another, directly or indirectly via intermediate cells. Electrical synapses are common in many brain structures such as the inferior olive, the subcoeruleus nucleus and the neocortex, between neurons and between glial cells. In the cortex, interneurons have been shown to be electrically coupled and proposed to participate in large, continuous cortical syncytia, as opposed to smaller spatial domains of electrically coupled cells. However, to explore the significance of these findings it is imperative to map the electrical synaptic microcircuits, in analogy with in vitro studies on monosynaptic and disynaptic chemical coupling. Since "walking” from cell to cell over large distances with a glass pipette is challenging, microinjection of (fluorescent) dyes diffusing through gap-junctions remains so far the only method available to decipher such microcircuits even though technical limitations exist. Based on circuit theory, we derive analytical descriptions of the AC electrical coupling in networks of isopotential cells. We then suggest an operative electrophysiological protocol to distinguish between direct electrical connections and connections involving one or more intermediate cells. This method allows inferring the number of intermediate cells, generalizing the conventional coupling coefficient, which provides limited information. We validate our method through computer simulations, theoretical and numerical methods and electrophysiological paired recording

Inferring connection proximity in networks of electrically coupled cells by subthreshold frequency response analysis

Electrical synapses continuously transfer signals bi-directionally from one cell to another, directly or indirectly via intermediate cells. Electrical synapses are common in many brain structures such as the inferior olive, the subcoeruleus nucleus and the neocortex, between neurons and between glial cells. In the cortex, interneurons have been shown to be electrically coupled and proposed to participate in large, continuous cortical syncytia, as opposed to smaller spatial domains of electrically coupled cells. However, to explore the significance of these findings it is imperative to map the electrical synaptic microcircuits, in analogy with in vitro studies on monosynaptic and disynaptic chemical coupling. Since "walking" from cell to cell over large distances with a glass pipette is challenging, microinjection of (fluorescent) dyes diffusing through gap-junctions remains so far the only method available to decipher such microcircuits even though technical limitations exist. Based on circuit theory, we derive analytical descriptions of the AC electrical coupling in networks of isopotential cells. We then suggest an operative electrophysiological protocol to distinguish between direct electrical connections and connections involving one or more intermediate cells. This method allows inferring the number of intermediate cells, generalizing the conventional coupling coefficient, which provides limited information. We validate our method through computer simulations, theoretical and numerical methods and electrophysiological paired recordings. \ua9 Springer Science+Business Media, LLC 2007

Intermittent Theta Burst Stimulation: Application to Spinal Cord Injury Rehabilitation and Computational Modeling

Loss of motor function from spinal cord injuries (SCI) results in loss of independence. Rehabilitation efforts are targeted to enhance the ability to perform activities of daily living (ADLs), but outcomes from physical therapy alone are often insufficient. Neuromodulation techniques that induce neuroplasticity may push the limits on recovery. Neuromodulation by intermittent theta burst transcranial magnetic stimulation (iTBS) induces neuroplasticity by increasing corticomotor excitability, though this has most frequently been studied with motor targets and on individuals not in need of rehabilitation. Increased corticomotor excitability is associated with motor learning. The response to iTBS, however, is highly variable and unpredictable, while the mechanisms are not well understood. Studies have proposed brain anatomy and individual subject differences as a source of variability but have not quantified the effects. Existing models have not incorporated known neurotransmitter changes at the synaptic level to pair mechanisms to cell output in a neural circuit. To use iTBS in practical rehabilitative efforts, the technique must either be consistent, have a predictable responsiveness, or present with enough mechanistic understanding to improve its efficacy. To that effect, this study has two primary objectives for the improvement of rehabilitation techniques. The first is to establish how iTBS affects both a motor target and population that typically undergoes physical rehabilitation often with unsatisfactory outcomes, in this case the biceps brachii in individuals with SCI and relate the empirical effects of iTBS to individual anatomy. This will establish the consistency of the technique and predictability of its effects, relevant to rehabilitative efforts. The secondary objective is to create the foundation of a model that exhibits circuit organization, which would start the development of a motor neuroplasticity functional unit with simulation of the synaptic long-term potentiation (LTP) like effects of iTBS. Summary of Methods: iTBS was performed targeting the biceps, on multiple cohorts, with changes in motor evoked potential amplitude (MEP) tracked after sham and active intervention. This was compared between nonimpaired individuals and those with SCI. Furthermore, iTBS of both biceps and first dorsal interosseus (FDI) was compared to simulation of TMS on MRI derived head models to establish the impact of individualized neuroanatomy. Finally, a motor canonical neural circuit was programmed to display fundamental physiological spiking behavior of membrane potentials. Summary of Results: iTBS did facilitate corticomotor excitability in the biceps of nonimpaired individuals and in those with SCI. iTBS had no group-wide effect on the FDI, highlighting the variability in response to the protocol. TMS response (motor thresholds) and iTBS response (change in MEPs) both were related to parameters extracted from MRI-derived head models representing variations in individual neuroanatomy. The neural circuit model represents a canonical networked unit. In the future, this can be further tuned to exhibit biological variability and generate population-based values being run in parallel, while matching the understood mechanisms of neuroplasticity: disinhibition and LTP. Conclusion: These studies provide missing information of iTBS responsivity by (1) determining group-wide responsiveness in a clinically relevant target; (2) establishing individual level influences that affect responsivity which can be measured prior to iTBS; and (3) beginning design of a tool to test a single neural circuit and its mechanistic responses