Timothy H. Lucas

Transparent and flexible low noise graphene electrodes for simultaneous electrophysiology and neuroimaging

Calcium imaging is a versatile experimental approach capable of resolving single neurons with single-cell spatial resolution in the brain. Electrophysiological recordings provide high temporal, but limited spatial resolution, because of the geometrical inaccessibility of the brain. An approach that integrates the advantages of both techniques could provide new insights into functions of neural circuits. Here, we report a transparent, flexible neural electrode technology based on graphene, which enables simultaneous optical imaging and electrophysiological recording. We demonstrate that hippocampal slices can be imaged through transparent graphene electrodes by both confocal and two-photon microscopy without causing any light-induced artefacts in the electrical recordings. Graphene electrodes record high-frequency bursting activity and slow synaptic potentials that are hard to resolve by multicellular calcium imaging. This transparent electrode technology may pave the way for high spatio-temporal resolution electro-optic mapping of the dynamic neuronal activity.

Bioresorbable silicon electronics for transient spatiotemporal mapping of electrical activity from the cerebral cortex

Bioresorbable silicon electronics technology offers unprecedented opportunities to deploy advanced implantable monitoring systems that eliminate risks, cost and discomfort associated with surgical extraction. Applications include post-operative monitoring and transient physiologic recording after percutaneous or minimally invasive placement of vascular, cardiac, orthopedic, neural or other devices. We present an embodiment of these materials in both passive and actively addressed arrays of bioresorbable silicon electrodes with multiplexing capabilities, that record in vivo electrophysiological signals from the cortical surface and the subgaleal space. The devices detect normal physiologic and epileptiform activity, both in acute and chronic recordings. Comparative studies show sensor performance comparable to standard clinical systems and reduced tissue reactivity relative to conventional clinical electrocorticography (ECoG) electrodes. This technology offers general applicability in neural interfaces, with additional potential utility in treatment of disorders where transient monitoring and modulation of physiologic function, implant integrity and tissue recovery or regeneration are required.

Dynamic Network Drivers of Seizure Generation, Propagation and Termination in Human Neocortical Epilepsy

The epileptic network is characterized by pathologic, seizure-generating ‘foci’ embedded in a web of structural and functional connections. Clinically, seizure foci are considered optimal targets for surgery. However, poor surgical outcome suggests a complex relationship between foci and the surrounding network that drives seizure dynamics. We developed a novel technique to objectively track seizure states from dynamic functional networks constructed from intracranial recordings. Each dynamical state captures unique patterns of network connections that indicate synchronized and desynchronized hubs of neural populations. Our approach suggests that seizures are generated when synchronous relationships near foci work in tandem with rapidly changing desynchronous relationships from the surrounding epileptic network. As seizures progress, topographical and geometrical changes in network connectivity strengthen and tighten synchronous connectivity near foci—a mechanism that may aid seizure termination. Collectively, our observations implicate distributed cortical structures in seizure generation, propagation and termination, and may have practical significance in determining which circuits to modulate with implantable devices.

Virtual Cortical Resection Reveals Push-Pull Network Control Preceding Seizure Evolution

In ∼20 million people with drug-resistant epilepsy, focal seizures originating in dysfunctional brain networks will often evolve and spread to surrounding tissue, disrupting function in otherwise normal brain regions. To identify network control mechanisms that regulate seizure spread, we developed a novel tool for pinpointing brain regions that facilitate synchronization in the epileptic network. Our method measures the impact of virtually resecting putative control regions on synchronization in a validated model of the human epileptic network. By applying our technique to time-varying functional networks, we identified brain regions whose topological role is to synchronize or desynchronize the epileptic network. Our results suggest that greater antagonistic push-pull interaction between synchronizing and desynchronizing brain regions better constrains seizure spread. These methods, while applied here to epilepsy, are generalizable to other brain networks and have wide applicability in isolating and mapping functional drivers of brain dynamics in health and disease.

Theta and High-Frequency Activity Mark Spontaneous Recall of Episodic Memories

Humans possess the remarkable ability to search their memory, allowing specific past episodes to be re-experienced spontaneously. Here, we administered a free recall test to 114 neurosurgical patients and used intracranial theta and high-frequency activity (HFA) to identify the spatiotemporal pattern of neural activity underlying spontaneous episodic retrieval. We found that retrieval evolved in three electrophysiological stages composed of: (1) early theta oscillations in the right temporal cortex, (2) increased HFA in the left hemisphere including the medial temporal lobe (MTL), left inferior frontal gyrus, as well as the ventrolateral temporal cortex, and (3) motor/language activation during vocalization of the retrieved item. Of these responses, increased HFA in the left MTL predicted recall performance. These results suggest that spontaneous recall of verbal episodic memories involves a spatiotemporal pattern of spectral changes across the brain; however, high-frequency activity in the left MTL represents a final common pathway of episodic retrieval.

Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy

Noninvasive glutamate brain imaging (GluCEST) can localize seizure foci to one hemisphere in patients with temporal lobe epilepsy. Toward visualizing the focus Many seizures, especially those that originate in the brain’s temporal lobe, start at a single spot in the brain. If drugs fail, excision of this region can often provide relief from seizures. A new imaging method that harnesses the power of a 7-T magnet shows promise in locating hard-to-find epileptic foci by visualizing the neurotransmitter glutamate. In a pilot study, the authors used glutamate chemical exchange saturation transfer (GluCEST), a very high resolution magnetic resonance imaging contrast method, to measure how much glutamate was in the hippocampi of four patients with epilepsy. Glutamate is elevated in epileptic foci. The amount of glutamate was clearly higher in one of the hippocampi in all four patients, and confirmatory methods (electroencephalography or magnetic resonance spectra) verified independently that the hippocampus with the elevated glutamate was located in the same hemisphere as the epileptic focus. Although the authors have only taken a first step toward noninvasively finding epileptic foci, their demonstration that GluCEST can localize small brain hot spots of high glutamate is promising. This approach can potentially allow a higher rate of successful surgeries in this difficult disease. When neuroimaging reveals a brain lesion, drug-resistant epilepsy patients show better outcomes after resective surgery than do the one-third of drug-resistant epilepsy patients who have normal brain magnetic resonance imaging (MRI). We applied a glutamate imaging method, GluCEST (glutamate chemical exchange saturation transfer), to patients with nonlesional temporal lobe epilepsy based on conventional MRI. GluCEST correctly lateralized the temporal lobe seizure focus on visual and quantitative analyses in all patients. MR spectra, available for a subset of patients and controls, corroborated the GluCEST findings. Hippocampal volumes were not significantly different between hemispheres. GluCEST allowed high-resolution functional imaging of brain glutamate and has potential to identify the epileptic focus in patients previously deemed nonlesional. This method may lead to improved clinical outcomes for temporal lobe epilepsy as well as other localization-related epilepsies.

Direct Brain Stimulation Modulates Encoding States and Memory Performance in Humans

People often forget information because they fail to effectively encode it. Here, we test the hypothesis that targeted electrical stimulation can modulate neural encoding states and subsequent memory outcomes. Using recordings from neurosurgical epilepsy patients with intracranially implanted electrodes, we trained multivariate classifiers to discriminate spectral activity during learning that predicted remembering from forgetting, then decoded neural activity in later sessions in which we applied stimulation during learning. Stimulation increased encoding-state estimates and recall if delivered when the classifier indicated low encoding efficiency but had the reverse effect if stimulation was delivered when the classifier indicated high encoding efficiency. Higher encoding-state estimates from stimulation were associated with greater evidence of neural activity linked to contextual memory encoding. In identifying the conditions under which stimulation modulates memory, the data suggest strategies for therapeutically treating memory dysfunction.

Reducing surgical site infections following craniotomy: examination of the use of topical vancomycin

OBJECT Although the use of topical vancomycin has been shown to be safe and effective for reducing postoperative infection rates in patients after spine surgery, its use in cranial wounds has not been studied systematically. The authors hypothesized that topical vancomycin, applied in powder form directly to the subgaleal space during closure, would reduce cranial wound infection rates. METHODS A cohort of 150 consecutive patients who underwent craniotomy was studied retrospectively. Seventy-five patients received 1 g of vancomycin powder applied in the subgaleal space at the time of closure. This group was compared with 75 matched-control patients who were accrued over the same time interval and did not receive vancomycin. The primary outcome measure was the presence of surgical site infection within 3 months. Secondary outcome measures included tissue pH from a subgaleal drain and vancomycin levels from the subgaleal space and serum. RESULTS Vancomycin was associated with significantly fewer surgical site infections (1 of 75) than was standard antibiotic prophylaxis alone (5 of 75; p < 0.05). Cultures were positive for typical skin flora species. As expected, local measured vancomycin concentrations peaked immediately after surgery (mean ± SD 499 ± 37 μg/ml) and gradually decreased over 12 hours. Vancomycin in the circulating serum remained undetectable. Subgaleal topical vancomycin was associated with a lower incidence of surgical site infections after craniotomy. The authors attribute this reduction in the infection rate to local vancomycin concentrations well above the minimum inhibitory concentration for antimicrobial efficacy. CONCLUSIONS Topical vancomycin is safe and effective for reducing surgical site infections after craniotomy. These data support the need for a prospective randomized examination of topical vancomycin in the setting of cranial surgery.

Myo-Cortical Crossed Feedback Reorganizes Primate Motor Cortex Output

The motor system is capable of adapting to changed conditions such as amputations or lesions by reorganizing cortical representations of peripheral musculature. To investigate the underlying mechanisms we induced targeted reorganization of motor output effects by establishing an artificial recurrent connection between a forelimb muscle and an unrelated site in the primary motor cortex (M1) of macaques. A head-fixed computer transformed forelimb electromyographic activity into proportional subthreshold intracortical microstimulation (ICMS) during hours of unrestrained volitional behavior. This conditioning paradigm stimulated the cortical site for a particular muscle in proportion to activation of another muscle and induced robust site- and input-specific reorganization of M1 output effects. Reorganization was observed within 25 min and could be maintained with intermittent conditioning for successive days. Control stimulation that was independent of muscle activity, termed “pseudoconditioning,” failed to produce reorganization. Preconditioning output effects were gradually restored during volitional behaviors following the end of conditioning. The ease of changing the relationship between cortical sites and associated muscle responses suggests that under normal conditions these relations are maintained through physiological feedback loops. These findings demonstrate that motor cortex outputs may be reorganized in a targeted and sustainable manner through artificial afferent feedback triggered from controllable and readily recorded muscle activity. Such cortical reorganization has implications for therapeutic treatment of neurological injuries.

Transorbital endoscopic amygdalohippocampectomy: a feasibility investigation.

OBJECT Resection of the hippocampus is the standard of care for medically intractable epilepsy in patients with mesial temporal sclerosis. Although temporal craniotomy in this setting is highly successful, the procedure carries certain immutable risks and may be associated with cognitive deficits related to cortical and white matter disruption. Alternative surgical approaches may reduce some of these risks by preserving the lateral temporal lobe. This study examined the feasibility of transorbital endoscopic amygdalohippocampectomy (TEA) as an alternative to open craniotomy in cadaveric specimens. METHODS TEA dissections were performed in 4 hemispheres from 2 injected cadaveric specimens fixed in alcohol. Quantitative predictions of the limits of exposure based on predissection imaging were compared with intradissection measurements. The extent of resection and angles of exposure during the dissection and on postdissection imaging were recorded. These measurements were validated with MRI studies from 10 epilepsy patients undergoing standard surgical evaluations. RESULTS The transorbital approach permitted direct access to the mesial temporal structures through the lateral orbital wall. Up to 97% of the hippocampal formation was resected with no brain retraction and minimal (mean 6.0 ± 1.4 mm) globe displacement. Lateral temporal lobe white matter tracts were preserved. CONCLUSIONS TEA permits hippocampectomy comparable to standard surgical approaches without disrupting the lateral temporal cortex or white matter. This novel approach is feasible in cadaveric specimens and warrants clinical investigation in carefully selected cases.