George C. McConnell

Nanoscale laminin coating modulates cortical scarring response around implanted silicon microelectrode arrays

Neural electrodes could significantly enhance the quality of life for patients with sensory and/or motor deficits as well as improve our understanding of brain functions. However, long-term electrical connectivity between neural tissue and recording sites is compromised by the development of astroglial scar around the recording probes. In this study we investigate the effect of a nanoscale laminin (LN) coating on Si-based neural probes on chronic cortical tissue reaction in a rat model. Tissue reaction was evaluated after 1 day, 1 week, and 4 weeks post-implant for coated and uncoated probes using immunohistochemical techniques to evaluate activated microglia/macrophages (ED-1), astrocytes (GFAP) and neurons (NeuN). The coating did not have an observable effect on neuronal density or proximity to the electrode surface. However, the response of microglia/macrophages and astrocytes was altered by the coating. One day post-implant, we observed an approximately 60% increase in ED-1 expression near LN-coated probe sites compared with control uncoated probe sites. Four weeks post-implant, we observed an approximately 20% reduction in ED-1 expression along with an approximately 50% reduction in GFAP expression at coated relative to uncoated probe sites. These results suggest that LN has a stimulatory effect on early microglia activation, accelerating the phagocytic function of these cells. This hypothesis is further supported by the increased mRNA expression of several pro-inflammatory cytokines (TNF-alpha, IL-1 and IL-6) in cultured microglia on LN-bound Si substrates. LN immunostaining of coated probes immediately after insertion and retrieval demonstrates that the coating integrity is not compromised by the shear force during insertion. We speculate, based on these encouraging results, that LN coating of Si neural probes could potentially improve chronic neural recordings through dispersion of the astroglial scar.

Effective Deep Brain Stimulation Suppresses Low-Frequency Network Oscillations in the Basal Ganglia by Regularizing Neural Firing Patterns

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for the motor symptoms of Parkinsons disease (PD). The effects of DBS depend strongly on stimulation frequency: high frequencies (>90 Hz) improve motor symptoms, while low frequencies (<50 Hz) are either ineffective or exacerbate symptoms. The neuronal basis for these frequency-dependent effects of DBS is unclear. The effects of different frequencies of STN-DBS on behavior and single-unit neuronal activity in the basal ganglia were studied in the unilateral 6-hydroxydopamine lesioned rat model of PD. Only high-frequency DBS reversed motor symptoms, and the effectiveness of DBS depended strongly on stimulation frequency in a manner reminiscent of its clinical effects in persons with PD. Quantification of single-unit activity in the globus pallidus externa (GPe) and substantia nigra reticulata (SNr) revealed that high-frequency DBS, but not low-frequency DBS, reduced pathological low-frequency oscillations (∼9 Hz) and entrained neurons to fire at the stimulation frequency. Similarly, the coherence between simultaneously recorded pairs of neurons within and across GPe and SNr shifted from the pathological low-frequency band to the stimulation frequency during high-frequency DBS, but not during low-frequency DBS. The changes in firing patterns in basal ganglia neurons were not correlated with changes in firing rate. These results indicate that high-frequency DBS is more effective than low-frequency DBS, not as a result of changes in firing rate, but rather due to its ability to replace pathological low-frequency network oscillations with a regularized pattern of neuronal firing.

Extraction Force and Cortical Tissue Reaction of Silicon Microelectrode Arrays Implanted in the Rat Brain

Micromotion of implanted silicon multielectrode arrays (Si MEAs) is thought to influence the inflammatory response they elicit. The degree of strain that micromotion imparts on surrounding tissue is related to the extent of mechanical integration of the implanted electrodes with the brain. In this study, we quantified the force of extraction of implanted four shank Michigan electrodes in adult rat brains and investigated potential cellular and extracellular matrix contributors to tissue-electrode adhesion using immunohistochemical markers for microglia, astrocytes and extracellular matrix deposition in the immediate vicinity of the electrodes. Our results suggest that the peak extraction force of the implanted electrodes increases significantly from the day of implantation (day 0) to the day of extraction (day 7 and day 28 postimplantation) (1.68 plusmn 0.54 g, 3.99 plusmn 1.31 g, and 4.86 plusmn 1.49g, respectively; meanplusmnSD; n=4). For an additional group of four shank electrode implants with a closer intershank spacing we observed a significant increase in peak extraction force on day 28 postimplantation compared to day 0 and day 7 postimplantation (5.56 plusmn 0.76 g, 0.37 plusmn 0.12 g and 1.87 plusmn 0.88 g, respectively; n=4). Significantly, only glial fibrillary acidic protein (GFAP) expression was correlated with peak extraction force in both electrode designs of all the markers of astroglial scar studied. For studies that try to model micromotion-induced strain, our data implies that adhesion between tissue and electrode increases after implantation and sheds light on the nature of implanted electrode-elicited brain tissue reaction

Characterizing Effects of Subthalamic Nucleus Deep Brain Stimulation on Methamphetamine-Induced Circling Behavior in Hemi-Parkinsonian Rats

The unilateral 6-hydroxydopamine (6-OHDA) lesioned rat model is frequently used to study the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) for the treatment of Parkinsons disease. However, systematic knowledge of the effects of DBS parameters on behavior in this animal model is lacking. The goal of this study was to characterize the effects of DBS on methamphetamine-induced circling in the unilateral 6-OHDA lesioned rat. DBS parameters tested include stimulation amplitude, stimulation frequency, methamphetamine dose, stimulation polarity, and anatomical location of the electrode. When an appropriate stimulation amplitude and dose of methamphetamine were applied, high-frequency stimulation (>; 130 Hz), but not low frequency stimulation (<; 10 Hz), reversed the bias in ipsilateral circling without inhibiting movement. This characteristic frequency tuning profile was only generated when at least one electrode used during bipolar stimulation was located within the STN. No difference was found between bipolar stimulation and monopolar stimulation when the most effective electrode contact was selected, indicating that monopolar stimulation could be used in future experiments. Methamphetamine-induced circling is a simple, reliable, and sensitive behavioral test and holds potential for high-throughput study of the effects of STN DBS in unilaterally lesioned rats.

Failure to suppress low-frequency neuronal oscillatory activity underlies the reduced effectiveness of random patterns of deep brain stimulation

Subthalamic nucleus (STN) deep brain stimulation (DBS) is an established treatment for the motor symptoms of Parkinsons disease (PD). However, the mechanisms of action of DBS are unknown. Random temporal patterns of DBS are less effective than regular DBS, but the neuronal basis for this dependence on temporal pattern of stimulation is unclear. Using a rat model of PD, we quantified the changes in behavior and single-unit activity in globus pallidus externa and substantia nigra pars reticulata during high-frequency STN DBS with different degrees of irregularity. Although all stimulus trains had the same average rate, 130-Hz regular DBS more effectively reversed motor symptoms, including circling and akinesia, than 130-Hz irregular DBS. A mixture of excitatory and inhibitory neuronal responses was present during all stimulation patterns, and mean firing rate did not change during DBS. Low-frequency (7-10 Hz) oscillations of single-unit firing times present in hemiparkinsonian rats were suppressed by regular DBS, and neuronal firing patterns were entrained to 130 Hz. Irregular patterns of DBS less effectively suppressed 7- to 10-Hz oscillations and did not regularize firing patterns. Random DBS resulted in a larger proportion of neuron pairs with increased coherence at 7-10 Hz compared with regular 130-Hz DBS, which suggested that long pauses (interpulse interval >50 ms) during random DBS facilitated abnormal low-frequency oscillations in the basal ganglia. These results suggest that the efficacy of high-frequency DBS stems from its ability to regularize patterns of neuronal firing and thereby suppress abnormal oscillatory neural activity within the basal ganglia.

Endpoint forces obtained during intraspinal microstimulation of the cat lumbar spinal cord - experimental and biomechanical model results

We studied the structure of endpoint forces produced by microstimulation of the cat spinal cord, and from combinations of muscles using a biomechanical model of the cat hindlimb. The forces evoked by microstimulation were of four types. At some stimulation sites, the force patterns exhibited a point of convergence where the active endpoint force was zero. The endpoint forces produced by activating combinations of muscles in the biomechanical model were of types similar to the experimental ones, although they demonstrated points of convergence in locations not observed experimentally. These results suggest that the spinal circuitry uses a subset of the possible muscular combinations.

Frequency-dependent, transient effects of subthalamic nucleus deep brain stimulation on methamphetamine-induced circling and neuronal activity in the hemiparkinsonian rat

HighlightsHigh frequency STN DBS resulted in transient circling contralateral to the lesion.High frequency STN DBS elicited transient changes in activity of GPe and SNr neurons.Distinct mechanisms were responsible for transient and sustained responses. ABSTRACT Methamphetamine‐induced circling is used to quantify the behavioral effects of subthalamic nucleus (STN) deep brain stimulation (DBS) in hemiparkinsonian rats. We observed a frequency‐dependent transient effect of DBS on circling, and quantified this effect to determine its neuronal basis. High frequency STN DBS (75–260 Hz) resulted in transient circling contralateral to the lesion at the onset of stimulation, which was not sustained after the first several seconds of stimulation. Following the transient behavioral change, DBS resulted in a frequency‐dependent steady‐state reduction in pathological ipsilateral circling, but no change in overall movement. Recordings from single neurons in globus pallidus externa (GPe) and substantia nigra pars reticulata (SNr) revealed that high frequency, but not low frequency, STN DBS elicited transient changes in both firing rate and neuronal oscillatory power at the stimulation frequency in a subpopulation of GPe and SNr neurons. These transient changes were not sustained, and most neurons exhibited a different response during the steady‐state phase of DBS. During the steady‐state, DBS produced elevated neuronal oscillatory power at the stimulus frequency in a majority of GPe and SNr neurons, and the increase was more pronounced during high frequency DBS than during low frequency DBS. Changes in oscillatory power during both transient and steady‐state DBS were highly correlated with changes in firing rates. These results suggest that distinct neural mechanisms were responsible for transient and sustained behavioral responses to STN DBS. The transient contralateral turning behavior following the onset of high frequency DBS was paralleled by transient changes in firing rate and oscillatory power in the GPe and SNr, while steady‐state suppression of ipsilateral turning was paralleled by sustained increased synchronization of basal ganglia neurons to the stimulus pulses. Our analysis of distinct frequency‐dependent transient and steady‐state responses to DBS lays the foundation for future mechanistic studies of the immediate and persistent effects of DBS.

Stimulation location within the substantia nigra pars reticulata differentially modulates gait in hemiparkinsonian rats

Deep brain stimulation (DBS) improves the distal motor symptoms of Parkinsons disease, but long-term improvements in gait and postural disturbances are less pronounced. The effects of stimulation location, within the large nuclear region of the substantia nigra pars reticulata (SNr), and stimulation parameters on improvement in gait are unclear, and this lack of foundational knowledge hinders the application and optimization of SNr DBS. We quantified the effects of medial vs. lateral SNr DBS on methamphetamine-induced circling in hemiparkinsonian rats to test the hypothesis that stimulation location differentially modulates axial symptoms. The frequency tuning curves showed opposite trends with stimulation frequency; during high frequency stimulation, medial SNr DBS decreased ipsilateral circling, while lateral SNr DBS had no effect on circling. As well, we quantified the effects of 130 Hz SNr DBS on gait to test the hypothesis that SNr DBS location differentially modulates gait. High frequency DBS of the medial SNr, but not lateral SNr, improved the rats ability to maintain walking speed. The therapeutic effects of medial SNr DBS appeared to improve with time on the same order as clinical studies (>10 min). These results suggest that improvement in gait depends on the location of the electrodes (medial vs. lateral SNr) with a time course for improvement reminiscent of human data and provide a rational basis for the appropriate selection of implant site and stimulation parameters for SNr DBS.

Experimental and biomechanical model force fields produced by intraspinal microstimulation of the cat lumbar spinal cord

Using a biomechanical model of the cat hindlimb, we studied patterns of endpoint forces created by all muscle combinations of fourteen selected muscles, and compared them to the force patterns produced by intraspinal microstimulation of the lumbar spinal gray matter. We ran the model with two different activation schemes for the muscles. The first run used combinations of the fourteen selected muscles stimulated at the same level of activation. The second run used combinations where muscle forces were normalized to produce the same maximum end-point force. These results were compared to force field patterns obtained experimentally during intraspinal microstimulation. Although there were slight variations in the force patterns produced, both methods converged to four dominant patterns. When muscles in the model were normalized, some force patterns were found that were not observed experimentally. These results show the significance of specific levels of muscle activation to the production of the experimental patterns.

Irregular high frequency patterns decrease the effectiveness of deep brain stimulation in a rat model of Parkinson's disease

Deep brain stimulation (DBS) is an effective treatment of Parkinsons disease, but its mechanisms are still unclear. To test the hypothesis that DBS alleviates motor symptoms by regularizing neuronal firing, we applied regular frequency stimulation between 5-260 Hz as well as irregular high frequency stimulation with an average rate of 130Hz to rats with unilateral 6-hydroxydopamine (6-OHDA) lesions. We found that high frequency regular stimulation above 130Hz was more effective than both low frequency stimulation and high frequency irregular stimulation at normalizing pathological circling behavior. Our results support the hypothesis that DBS is effective because it is able to mask pathological firing patterns within the basal ganglia, and highlight the importance of the temporal pattern in addition to the rate of stimulation.