Imaging the large-scale and cellular response to focal traumatic brain injury in mouse neocortex.

Traumatic brain injury (TBI) affects neural function at the local injury site and also at distant, connected brain areas. However, the real-time neural dynamics in response to injury and subsequent effects on sensory processing and behavior are not fully resolved, especially across a range of spatial scales. We used in vivo calcium imaging in awake, head-restrained male and female mice to measure large-scale and cellular resolution neuronal activation, respectively, in response to a mild/moderate TBI induced by focal controlled cortical impact (CCI) injury of the motor cortex (M1). Widefield imaging revealed an immediate CCI-induced activation at the injury site, followed by a massive slow wave of calcium signal activation that traveled across the majority of the dorsal cortex within approximately 30 s. Correspondingly, two-photon calcium imaging in primary somatosensory cortex (S1) found strong activation of neuropil and neuronal populations during the CCI-induced traveling wave. A depression of calcium signals followed the wave, during which we observed atypical activity of a sparse population of S1 neurons. Longitudinal imaging in the hours and days after CCI revealed increases in the area of whisker-evoked sensory maps at early time points, in parallel to decreases in cortical functional connectivity and behavioral measures. Neural and behavioral changes mostly recovered over hours to days in our M1-TBI model, with a more lasting decrease in the number of active S1 neurons. Our results in unanesthetized mice describe novel spatial and temporal neural adaptations that occur at cortical sites remote to a focal brain injury.

Dexmedetomidine-mediated sleep phase modulation ameliorates motor and cognitive performance in a chronic blast-injured mouse model.

Multiple studies have shown that blast injury is followed by sleep disruption linked to functional sequelae. It is well established that improving sleep ameliorates such functional deficits. However, little is known about longitudinal brain activity changes after blast injury. In addition, the effects of directly modulating the sleep/wake cycle on learning task performance after blast injury remain unclear. We hypothesized that modulation of the sleep phase cycle in our injured mice would improve post-injury task performance. Here, we have demonstrated that excessive sleep electroencephalographic (EEG) patterns are accompanied by prominent motor and cognitive impairment during acute stage after secondary blast injury (SBI) in a mouse model. Over time we observed a transition to more moderate and prolonged sleep/wake cycle disturbances, including changes in theta and alpha power. However, persistent disruptions of the non-rapid eye movement (NREM) spindle amplitude and intra-spindle frequency were associated with lasting motor and cognitive deficits. We, therefore, modulated the sleep phase of injured mice using subcutaneous (SC) dexmedetomidine (Dex), a common, clinically used sedative. Dex acutely improved intra-spindle frequency, theta and alpha power, and motor task execution in chronically injured mice. Moreover, dexmedetomidine ameliorated cognitive deficits a week after injection. Our results suggest that SC Dex might potentially improve impaired motor and cognitive behavior during daily tasks in patients that are chronically impaired by blast-induced injuries.

Identifying mild traumatic brain injury using measures of frequency-specified networks.

Objective. Early diagnosis of mild traumatic brain injury (mTBI) is challenging, yet crucial for providing patients with timely treatments and minimizing the risks of developing injury-related disorders. To tackle this problem, this paper presents a framework based on measures of frequency-specified brain functional networks identifying mTBI.Approach. Cortical activity of 15 control and 15 injury Thy1-GCaMP6s mice are recorded, using widefield calcium imaging, prior to and 20 minutes after inducing injury. Power spectral distribution (PSD) of the recorded cortical activities is examined, and the frequency bands with significant difference in PSD between the injury and control groups are identified. Frequency-specified functional networks are then constructed. Employing graph theoretical analysis, various network measures from the constructed frequency-specified functional networks are extracted and used as features. Several classifiers are utilized to evaluate the performance of the computed network measures, either individually or collectively as features, to classify mTBI from control.Main results. Spectral analysis reveals the presence of two dominant frequency bands (low:<1Hz) and high: [1-8] Hz) in the cortical activities recorded via calcium imaging. Comparison of the brain networks of control and injury groups shows significant reduction (p < 0.05) in global functional connectivity following injury, specially for the high frequency band network. Interestingly, graph measures of the high frequency band network provided higher classification accuracy results, compared to those computed from the low frequency band network, suggesting that mTBI network-based features are frequency dependent. Using all network measures collectively as a multi-measure feature vector and a convolutional neural networks classifier, a model for identifying mTBI is developed, offering an average classification accuracy of 97.28%.Significance. Results signifies the importance of considering frequency-specific analysis in functional networks for mTBI identification, and demonstrate the possibility of using network measures for early mTBI diagnosis.

Fabrication of a Multilayer Implantable Cortical Microelectrode Probe to Improve Recording Potential.

Intracortical neural probes are a key enabling technology for acquiring high fidelity neural signals within the cortex. They are viewed as a crucial component of brain-computer interfaces (BCIs) in order to record electrical activities from neurons within the brain. Smaller, more flexible, polymer-based probes have been investigated for their potential to limit the acute and chronic neural tissue response. Conventional methods of patterning electrodes and connecting traces on a single supporting layer can limit the number of recording sites which can be defined, particularly when designing narrower probes. We present a novel strategy of increasing the number of recording sites without proportionally increasing the size of the probe by using a multilayer fabrication process to vertically layer recording traces on multiple Parylene support layers, allowing more recording traces to be defined on a smaller probe width. Using this approach, we are able to define 16 electrodes on 4 supporting layers (4 electrodes per layer), each with a 30 µm diameter recording window and 5 µm wide connecting trace defined by conventional LWUV lithography, on an 80 µm wide by 9 µm thick microprobe. Prior to in vitro and in vivo validation, the multilayer probes are electrically characterized via impedance spectroscopy and evaluating crosstalk between adjacent layers. Demonstration of acute in vitro recordings in a cerebral organoid model and in vivo recordings in a murine model indicate the probe's capability for single unit recordings. This work demonstrates the ability to fabricate smaller, more compliant neural probes without sacrificing electrode density.