David J. Guggenmos

Restoration of function after brain damage using a neural prosthesis

Significance Closed-loop systems, or brain–machine–brain interfaces (BMBIs), have not been widely developed for brain repair. In this study, we targeted spared motor and somatosensory regions of the rat brain after traumatic brain injury for establishment of a functional bridge using a battery-powered microdevice. The results show that by using discriminated action potentials as a trigger for stimulating a distant cortical location, rapid recovery of fine motor skills is facilitated. This study provides strong evidence that BMBIs can be used to bridge damaged neural pathways functionally and promote recovery after brain injury. Although this study is restricted to a rodent model of TBI, it is likely that the approach will also be applicable to other types of acquired brain injuries. Neural interface systems are becoming increasingly more feasible for brain repair strategies. This paper tests the hypothesis that recovery after brain injury can be facilitated by a neural prosthesis serving as a communication link between distant locations in the cerebral cortex. The primary motor area in the cerebral cortex was injured in a rat model of focal brain injury, disrupting communication between motor and somatosensory areas and resulting in impaired reaching and grasping abilities. After implantation of microelectrodes in cerebral cortex, a neural prosthesis discriminated action potentials (spikes) in premotor cortex that triggered electrical stimulation in somatosensory cortex continuously over subsequent weeks. Within 1 wk, while receiving spike-triggered stimulation, rats showed substantially improved reaching and grasping functions that were indistinguishable from prelesion levels by 2 wk. Post hoc analysis of the spikes evoked by the stimulation provides compelling evidence that the neural prosthesis enhanced functional connectivity between the two target areas. This proof-of-concept study demonstrates that neural interface systems can be used effectively to bridge damaged neural pathways functionally and promote recovery after brain injury.

Reorganization of Motor Cortex after Controlled Cortical Impact in Rats and Implications for Functional Recovery

We report the results of controlled cortical impact (CCI) centered on the caudal forelimb area (CFA) of rat motor cortex to determine the feasibility of examining cortical plasticity in a spared cortical motor area (rostral forelimb area, RFA). We compared the effects of three CCI parameter sets (groups CCI-1, CCI-2, and CCI-3) that differed in impactor surface shape, size, and location, on behavioral recovery and RFA structural and functional integrity. Forelimb deficits in the limb contralateral to the injury were evident in all three CCI groups assessed by skilled reach and footfault tasks that persisted throughout the 35-day post-CCI assessment period. Nissl-stained coronal sections revealed that the RFA was structurally intact. Intracortical microstimulation experiments conducted at 7 weeks post-CCI demonstrated that RFA was functionally viable. However, the size of the forelimb representation decreased significantly in CCI-1 compared to the control group. Subdivided into component movement categories, there was a significant group effect for proximal forelimb movements. The RFA area reduction and reorganization are discussed in relation to possible diaschisis, and to compensatory functional behavior, respectively. Also, an inverse correlation between the anterior extent of the lesion and the size of the RFA was identified and is discussed in relation to corticocortical connectivity. The results suggest that CCI can be applied to rat CFA while sparing RFA. This CCI model can contribute to our understanding of neural plasticity in premotor cortex as a substrate for functional motor recovery.

A Miniaturized System for Spike-Triggered Intracortical Microstimulation in an Ambulatory Rat

This paper reports on a miniaturized system for spike-triggered intracortical microstimulation (ICMS) in an ambulatory rat. The head-mounted microdevice comprises a previously developed application-specific integrated circuit fabricated in 0.35-μm two-poly four-metal complementary metal-oxide-semiconductor technology, which is assembled and packaged on a miniature rigid-flex substrate together with a few external components for programming, supply regulation, and wireless operation. The microdevice operates autonomously from a single 1.55-V battery, measures 3.6 cm × 1.3 cm × 0.6 cm, weighs 1.7 g (including the battery), and is capable of stimulating as well as recording the neural response to ICMS in biological experiments with anesthetized laboratory rats. Moreover, it has been interfaced with silicon microelectrodes chronically implanted in the cerebral cortex of an ambulatory rat and successfully delivers electrical stimuli to the second somatosensory area when triggered by neural activity from the rostral forelimb area with a user-adjustable spike-stimulus time delay. The spike-triggered ICMS is further shown to modulate the neuronal firing rate, indicating that it is physiologically effective.

Effects of tongue force training on orolingual motor cortical representation

Previous research has demonstrated that training rats in a skilled reaching condition will induce task-related changes in the caudal forelimb area (CFA) of motor cortex. The purpose of the present study was to determine whether task-specific changes can be induced within the orofacial area of the motor cortex in rats. Specifically, we compared changes of the orofacial motor cortical representation in lick-trained rats to age-matched controls. For 1 month, six water-restricted Sprague-Dawley rats were trained to lick an isometric force-sensing disc at increasing forces for water reinforcement. The rats were trained daily for 6 min starting with forces of 1g, and increasing over the course of the month to 10, 15, 20, 25 and finally 30 g. One to three days following the last training session, the animals were subjected to a neurophysiological motor mapping procedure in which motor representations corresponding to the orofacial and adjacent areas were defined using intracortical microstimulation (ICMS) techniques. We found no statistical difference in the topographical representation of the control (mean=2.03 mm(2)) vs. trained (1.87 mm(2)) rats. This result indicates that force training alone is insufficient to drive changes in the size of the cortical representation. We also recorded the minimum current threshold required to elicit a motor response at each site of microstimulation. We found that the lick-trained rats had a significantly lower average minimum threshold (29.1+/-1.0 microA) for evoking movements related to the task compared to control rats (34.6+/-1.1 microA). These results indicate that while tongue force training alone does not produce lasting changes in the size of the orofacial cortical motor representation, tongue force training decreases the current thresholds necessary for eliciting an ICMS-evoked motor response.

Current Challenges Facing the Translation of Brain Computer Interfaces from Preclinical Trials to Use in Human Patients

Current research in brain computer interface (BCI) technology is advancing beyond preclinical studies, with trials beginning in human patients. To date, these trials have been carried out with several different types of recording interfaces. The success of these devices has varied widely, but different factors such as the level of invasiveness, timescale of recorded information, and ability to maintain stable functionality of the device over a long period of time all must be considered in addition to accuracy in decoding intent when assessing the most practical type of device moving forward. Here, we discuss various approaches to BCIs, distinguishing between devices focusing on control of operations extrinsic to the subject (e.g., prosthetic limbs, computer cursors) and those focusing on control of operations intrinsic to the brain (e.g., using stimulation or external feedback), including closed-loop or adaptive devices. In this discussion, we consider the current challenges facing the translation of various types of BCI technology to eventual human application.

Motor representations in the intact hemisphere of the rat are reduced after repetitive training of the impaired forelimb

Background. During recovery from a unilateral cortical stroke, spared cortical motor areas in the contralateral (intact) cerebral cortex are recruited. Preclinical studies have demonstrated that compensation with the less-impaired limb may have a detrimental inhibitory effect on the intact cortical hemisphere and could impede recovery of the more-impaired limb. However, evidence from detailed neurophysiological mapping studies in animal models is lacking. Objectives. The present study examines neurophysiological changes in the intact hemisphere of the rat following a unilateral ischemic infarct to cortical forelimb motor areas. Methods. A total of 8 rats were trained for 2 weeks on a reach and retrieval task prior to an ischemic infarct induced by the vasoconstrictor endothelin-1 injected into the cortical gray matter encompassing the 2 forelimb motor representations: the caudal forelimb area (CFA) and the rostral forelimb area (RFA). Animals were randomly assigned to an infarct/training group (n = 4) or an infarct/no-training group (ie, spontaneous recovery, n = 4). After a 5-week postinfarct period, motor areas of the intact hemisphere (CFA and RFA) were characterized using intracortical microstimulation techniques. The resulting maps of evoked movements were compared with maps derived from CFA and RFA in normal rats (normal, n = 5; normal/training, n = 4). Results. Compared with the normal/no-training group, CFA representations were significantly smaller in the infarct/training group but not in the infarct/no-training group. No significant differences were found in RFA. Conclusions. Repetitive training of the more-impaired forelimb during the postinfarct recovery period reduces the size of motor representations in the intact hemisphere.

A miniaturized brain-machine-spinal cord interface (BMSI) for closed-loop intraspinal microstimulation

This paper reports on a fully miniaturized brain-machine-spinal cord interface (BMSI) for closed-loop cortical control of intraspinal microstimulation (ISMS). The system incorporates two identical 4-channel modules, with each module comprising a neural recording front-end, embedded digital signal processing (DSP) unit, and programmable stimulating back-end. The DSP unit is capable of generating multichannel trigger signals for a wide array of ISMS triggering patterns based upon online discrimination of a programmable number of intracortical neural spikes within a pre-specified time bin via thresholding and time-amplitude windowing. The BMSI system is validated experimentally in a rat model of contusion spinal cord injury (SCI) by converting in real-time multichannel neural spikes recorded from the cerebral cortex into electrical stimuli delivered to the lumbar spinal cord below the level of the injury, resulting in distinct patterns of hindlimb muscle activation in the SCI rat.

Physiological basis of neuromotor recovery

Abstract Planning and execution of movement require coordinated activity from several interconnected cortical motor areas. When an area in this specialized motor network is damaged (e.g., through traumatic brain injury or ischemic event), motor network activity can be disrupted, leading to functional deficits. How the surviving motor network reorganizes to compensate for the injury and functional deficits can vary as a pathological consequence of the location and extent of the brain injury. The current chapter summarizes how neuroplasticity modifies motor networks in response to injury by focusing on the changes after an ischemic event in the primary motor cortex. Neuroanatomical and neurophysiological evidence in animal models and human stroke survivors is reviewed to demonstrate how injuries functionally impair motor networks, how motor networks compensate for injury to improve motor function, and how select therapies help facilitate recovery. Further research into these neuroplasticity mechanisms may one day help to develop more effective rehabilitation strategies.

Poster 202 A Translational Model of Traumatic Brain Injury: Motor Recovery from a Focal Controlled Cortical Impact to Primary Motor Cortex

for possible paraneoplastic etiology of diffuse demyelinating polyneuropathy. Conclusions: Paraneoplastic diffuse demyelinating peripheral neuropathy is an uncommon cause of progressive weakness in the setting of malignancy and should be considered in the differential diagnosis of otherwise unexplained weakness in individuals with cancer. Acute inpatient rehabilitation can also help improve functional outcomes. Level of Evidence: Level V