Advancing neurosurgery with image-guided robotics.

Robotic systems are being introduced into surgery to extend human ability. NeuroArm represents a potential change in the way surgery is performed; this is the first image-guided, MR-compatible surgical robot capable of both microsurgery and stereotaxy. This paper presents the first surgical application of neuroArm in an investigation of microsurgical performance, navigation accuracy, and Phase I clinical studies. To evaluate microsurgical performance, 2 surgeons performed microsurgery (splenectomy, bilateral nephrectomy, and thymectomy) in a rodent model using neuroArm and conventional techniques. Two senior residents served as controls, using the conventional technique only (8 rats were used in each of the 3 treatment groups; the 2 surgeons each treated 4 rats from each group). Total surgery time, blood loss, thermal injury, vascular injury, and animal death due to surgical error were recorded and converted to an overall performance score. All values are reported as the mean +/- SEM when normally distributed and as the median and interquartile range when not. Surgeons were slower using neuroArm (1047 +/- 69 seconds) than with conventional microsurgical techniques (814 +/- 54 seconds; p = 0.019), but overall performance was equal (neuroArm: 1110 +/- 82 seconds; microsurgery: 1075 +/- 136 seconds; p = 0.825). Using microsurgery, the surgeons had overall performance scores equal to those of the control resident surgeons (p = 0.141). To evaluate navigation accuracy, the localization error of neuroArm was compared with an established system. Nanoparticles were implanted at predetermined bilateral targets in a cadaveric model (4 specimens) using image guidance. The mean localization error of neuroArm (4.35 +/- 1.68 mm) proved equal to that of the conventional navigation system (10.4 +/- 2.79 mm; p = 0.104). Using the conventional system, the surgeon was forced to retract the biopsy tool to correct the angle of entry in 2 of 4 trials. To evaluate Phase I clinical integration, the role of neuroArm was progressively increased in 5 neurosurgical procedures. The impacts of neuroArm on operating room (OR) staff, hardware, software, and registration system performance were evaluated. NeuroArm was well received by OR staff and progressively integrated into patient cases, starting with draping in Case 1. In Case 2 and all subsequent cases, the robot was registered. It was used for tumor resection in Cases 3-5. Three incidents involving restrictive cable length, constrictive draping, and reregistration failure were resolved. In Case 5, the neuroArm safety system successfully mitigated a hardware failure. NeuroArm performs as well and as accurately as conventional techniques, with demonstrated safety technology. Clinical integration was well received by OR staff, and successful tumor resection validates the surgical applicability of neuroArm.

An image-guided magnetic resonance-compatible surgical robot.

OBJECTIVE: The past decade has witnessed the increasing application of robotics in surgery, yet there is no existing system that combines stereotaxy and microsurgery in an imaging environment. To fulfill this niche, we have designed and manufactured an image-guided robotic system that is compatible with magnetic resonance imaging. METHODS: The system conveys the sight, touch, and sound of surgery to an operator seated at a remote workstation. Motion scaling, tremor filtering, and precision robotics allow surgeons to rapidly attain technical proficiency while working at a spatial resolution of 50 to 100 microm instead of a few millimeters. This system has the potential to shift surgery from the organ toward the cellular level. RESULTS: By integrating the robot with images obtained during the procedure, the effects of surgery on both the lesion and brain are immediately revealed. CONCLUSION: We are providing technology to advance and transform surgery with the potential to improve patient outcome.

Expression of T-type calcium channel splice variants in human glioma.

In humans, three isoforms of the T-type (Ca(v)3.1) calcium-channel alpha(1) subunit have been reported as a result of alternate splicing of exons 25 and 26 in the III-IV linker region (Ca(v)3.1a, Ca(v)3.1b or Ca(v)3.1bc). In the present study, we report that human glioma express Ca(v)3.1 channels in situ, that splicing of these exons is uniquely regulated and that there is expression of a glioma-specific novel T-type variant (Ca(v)3.1ac). Seven human glioma samples were collected at surgery, RNA was extracted, and cDNA was produced for RT-PCR analysis. In addition, three glioma cell lines (U87, U563, and U251N), primary cultures of human fetal astrocytes, as well as adult and fetal human brain cDNA were used. Previously described Ca(v)3.1 splice variants were present in glioma samples, cultured cells and whole brain. Consistent with the literature, our results reveal that in the normal adult brain, Ca(v)3.1a transcripts predominate, while Ca(v)3.1b is mostly fetal-specific. RT-PCR results on glioma and glioma cell lines showed that Ca(v)3.1 expression in tumor cells resemble fetal brain expression pattern as Ca(v)3.1bc is predominantly expressed. In addition, we identified a novel splice variant, Ca(v)3.1ac, expressed in three glioma biopsies and one glioma cell line, but not in normal brain or fetal astrocytes. Transient expression of this variant demonstrates that Ca(v)3.1ac displays similar current-voltage and steady-state inactivation properties compared with Ca(v)3.1b, but a slower recovery from inactivation. Taken together, our data suggest glioma-specific Ca(v)3.1 gene regulation, which could possibly contribute to tumor pathogenesis.

Expression of voltage-gated Ca2+ channel subtypes in cultured astrocytes.

Transient intracellular [Ca(2+)] increases in astrocytes from influx and/or release from internal stores can release glutamate and thereby modulate synaptic transmission in adjacent neurons. Electrophysiological studies have shown that cultured astrocytes express voltage-dependent Ca(2+) channels but their molecular identities have remained unexplored. We therefore performed RT-PCR analysis with primers directed to different voltage-gated Ca(2+) channel alpha(1) subunits. In primary cultures of astrocytes, we detected mRNA transcripts for the alpha(1B) (N-type), alpha(1C) (L-type), alpha(1D) (L-type), alpha(1E) (R-type), and alpha(1G) (T-type), but not alpha(1A) (P/Q-type), voltage-gated Ca(2+) channels. We then used antibodies against all of the Ca(2+) channel subunits to confirm protein expression, via Western blots, and localization by means of immunocytochemistry. In Western blot analysis, we observed immunoreactive bands corresponding to the appropriate alpha(1) subunit proteins. Western blots showed an expression pattern similar to PCR results in that we detected proteins for the alpha(1B) (N-type), alpha(1C) (L-type), alpha(1D) (L-type), alpha(1E) (R-type), and alpha(1G) (T-type), but not alpha(1A) (P/Q-type). Using immunocytochemistry, we observed Ca(2+) channel expression for these subunits in punctate clusters on plasma membrane of GFAP-expressing astrocytes. These results confirm that cultured astrocytes express corresponding proteins to several high- and low-threshold Ca(2+) channels but not alpha(1A) (P/Q-type). Overall, our data indicate that astrocytes express multiple types of voltage-gated Ca(2+) channels, hinting at a complex regulation of Ca(2+) homeostasis in glial cells.

Non-ahr gene susceptibility Loci for porphyria and liver injury induced by the interaction of 'dioxin' with iron overload in mice.

Among the actions of 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in mice is the induction of hepatic porphyria. This is similar to the most common disease of this type in humans, sporadic porphyria cutanea tarda (PCT). Evidence is consistent with the actions of dioxin being mediated through binding to the aryl hydrocarbon receptor (AHR) with different Ahr alleles in mouse strains apparently accounting for differential downstream gene expression and susceptibility. However, studies of dioxin-induced porphyria and liver injury indicate that the mechanisms must involve interactions with other genes, perhaps associated with iron metabolism. We performed a quantitative trait locus (QTL) analysis of an F(2) cross between susceptible C57BL/6J (Ahr(b1) allele) and the highly resistant DBA/2 (Ahr(d) allele) strains after treatment with dioxin and iron. For porphyria we found QTLs on chromosomes 11 and 14 in addition to the Ahr gene (chromosome 12). Studies with C57BL/6.D2 Ahr(d) mice confirmed that the Ahr(d) allele alone did not completely negate the response. SWR mice are syngenic for the Ahr(d) allele with the DBA/2 strain but are susceptible to porphyria after elevation of hepatic iron. Analysis of SWRxD2 F(2) mice treated with iron and dioxin showed a QTL on chromosome 11, as well as finding other loci on chromosomes 1 (and possibly 9), for both porphyria and liver injury. These findings show for the first time the location of genes, other than Ahr, that modulate the mechanism of hepatic porphyria and injury caused by dioxin in mice. Orthologous loci may contribute to the pathogenesis of human sporadic PCT.