P. Charles Garell

Chronic Microelectrode Investigations of Normal Human Brain Physiology Using a Hybrid Depth Electrode

Neurosurgeons have unique access to in vivo human brain tissue, and in the course of clinical treatment important scientific advances have been made that further our understanding of normal brain physiology. In the modern era, microelectrode recordings have been used to systematically investigate the cellular properties of lateral temporal cerebral cortex. The current report describes a hybrid depth electrode (HDE) recording technique that was developed to enable neurosurgeons to simultaneously investigate normal cellular physiology during chronic intracranial EEG recordings. The HDE combines microelectrode and EEG recordings sites on a single shaft. Multiple microelectrode recordings are obtained from MRI defined brain sites and single-unit activity is discriminated from these data. To date, over 60 HDEs have been placed in 20 epilepsy surgery patients. Unique physiologic data have been gathered from neurons in numerous brain regions, including amygdala, hippocampus, frontal lobe, insula and Heschls gyrus. Functional activation studies were carried out without risking patient safety or comfort.

Elastic attention: enhanced, then sharpened response to auditory input as attentional load increases

A long debate in selective attention research is whether attention enhances sensory response or sharpens neural tuning by suppressing response to non-target input. In fact, both processes may occur as a function of load: an uncertain listener might use a broad attentional filter to enhance responses to all inputs (i.e., vigilance), yet employ sharpened tuning to focus on hard to discriminate targets. The present work used the greater signal gain, anatomical precision, and laterality separation of intracranial electrophysiological recordings (electrocorticograms) to investigate these competing effects. Data were recorded from acoustically-responsive cortex in the perisylvian region of a single hemisphere in five neurosurgery patients. Patients performed a dichotic listening task in which they alternately attended toward, away from, or completely ignored (silent reading) tones presented to designated ears at varying presentation rates. Comparisons between the grand-averaged event-related potential (ERP) waveforms show a striking change in the effect of selective auditory attention with attentional load. At slower presentation rates (low-load), ERPs were overall enhanced in response to both input channels and regardless of attended ear, including a significant enhancement of ipsilateral input. This result supports a broadly enhancing model of attention under low perceptual load conditions. At the fastest rate, however, only responses to attended inputs contralateral to grid location remained enhanced. This result supports an increasing suppression, or “sharpening,” of neural responses to non-targets with increasing attentional load. These data provide support for an elastic model of attention in which attentional scope narrows with increasing load.

The effects of attentional load on auditory ERPs recorded from human cortex

Responses to acoustic input were recorded from human temporal cortex using subdural electrodes in order to investigate in greater anatomical detail how attentional load modulates exogenous auditory responses. Four patient-volunteers performed a dichotic listening task in which they listened for rare frequency deviants in a series of tones presented to both ears at interstimulus intervals (ISIs) of 400, 800, and 2000 ms. Across all ISIs, stimuli presented contralateral to electrode location produced the strongest deflections in the averaged ERP at approximately 90 and 170 ms post-stimulus on average (labeled N90stg and P170stg). Maximal recording sites for these peaks most often occurred over the Sylvian fissure or the upper bank of the posterior superior temporal gyrus. Neither ISI nor selective attention exhibited substantial effects on peak latencies. However, as presentation rates increased (decreasing ISI), overall averaged event-related potential (ERP) amplitudes declined significantly, while attending to the contralateral stimulus significantly increased both the N90stg and P170stg peaks for most patients. This effect of attention increased with decreasing ISI for both components most clearly in the difference between the grand-average ERPs for attending to vs. ignoring the contralateral stimulus, and even more dramatically in the percentage ratio of that difference over the mean peak amplitude. This amplifying effect of attention with increasing load, along with its anatomical location, suggests that attention can enhance exogenous sources in auditory cortex.

PET measurement of changes in D2/D3 dopamine receptor binding in a nonhuman primate during chronic deep brain stimulation of the bed nucleus of the stria terminalis

UNLABELLED PET imaging is a powerful tool for measuring physiological changes in the brain during deep brain stimulation (DBS). In this work, we acquired five PET scans using a highly selective D2/D3 dopamine antagonist, 18F-fallypride, to track changes in dopamine receptor availability, as measured by the distribution volume ratio (DVR), through the course of DBS in the bed nucleus of the stria terminalis (BNST) in a nonhuman primate. METHODS PET scans were performed on a rhesus monkey with unilateral BNST stimulation during periods of baseline, chronic high frequency (130 Hz) and low frequency (50 Hz) DBS stimulation, and during a washout period between stimulation periods. A final scan was performed with the electrode stimulation starting 110 min into the scan. Whole brain parametric images of (18)F-fallypride DVR were calculated for each condition to track changes in both striatal and extrastriatal D2/D3 availability. RESULTS The monkey displayed significant increases in receptor binding throughout the brain during DBS relative to baseline for 130 and 50 Hz, with changes in DVR of: caudate 42%, 51%; putamen 56%, 57%; thalamus 33%, 49%; substantia nigra 29%, 26%; and prefrontal cortex 28%, 56%, respectively. Washout and post-stimulation scans revealed DVR values close to baseline values. Activating the stimulator midway through the final scan resulted in no statistically significant changes in binding. CONCLUSIONS PET neuroligand imaging has demonstrated the sensitivity to track changes in dopamine D2/D3 binding during the course of DBS. These methods show great potential for providing insight into the neurochemical consequences of DBS.

Electrocorticogram-Controlled Brain-Computer Interfaces in Patients with Temporary Subdural Electrode Implants

brain gene transfer. METHODS: AAV-XIAP or AAV-green fluorescent protein (GFP) (control) were first tested in cultured SY5Y cells for protection against toxicity from models of PD (proteasome inhibition, -synuclein) or HD (mutant Q111 huntington). AAV-XIAP or AAV-GFP were then injected into the substantia nigra (SNc) of normal rats given the systemic proteasome inhibitor PSI, which recapitulates many features of human PD. Transgenic mice expressing a mutant huntington exon 1 also received bilateral striatal injections of AAV-XIAP or AAV-GFP. RESULTS: In culture, PSI, -synuclein, and Q111 all caused 45–60% cell loss, which was completely blocked by AAV-XIAP. In the rat PSI model, a 50–60% loss of SNc dopaminergic neurons was observed in control animals, yet again, AAV-XIAP caused 100% neuronal protection. Transgenic HD mice showed a reduction in baseline motor behavior by rotorod testing compared with matched littermates. Although unaffected by AAV-GFP, AAV-XIAP caused an improvement in rotorod testing, and by 1 month after treatment, these mice reach levels of normal mice. This effect was sustained for 3 months, which was the entire lifespan of these animals. There was a corresponding increased survival in AAV-XIAP HD mice compared with controls. CONCLUSION: AAV-XIAP seems to be a very effective agent for neuroprotection in a newly described rat model of PD, and in transgenic HD mice, it reverses baseline motor deficits and improves survival. With the interest in neuroprotection in PD, the lack of effective therapy for HD, and our recent demonstration that AAV gene therapy can be safe in human PD, these strategies may hold therapeutic promise.