Full-Endoscopic Removal of Migrated and Pseudoarthrotic Lumbar Interbody Cages: Case Reports and Technical Note.

BACKGROUND: The removal of a lumbar interbody cage in revision spine surgery can be challenging, as there is an increased risk of nerve injury and a protracted outcome. The aim of this study was to evaluate the feasibility and preliminary results of uniportal full-endoscopic surgery for the removal of migrated and/or pseudarthrotic lumbar interbody cages. METHODS: Three complex revision surgery cases with migrated and pseudarthrotic lumbar interbody cages are presented, and the endoscopic surgical technique is described. The clinical outcome was assessed with a visual analog scale and Oswestry Disability Index (ODI) at 1-, 3-, 6-, and 12-month follow-up, while the radiologic outcome was assessed with pre- and postoperative x-ray and computed tomographic images. Full-endoscopic surgery was performed to extract the interbody cage, bypassing scar tissue of previous surgeries with the trans-Kambin approach. Foraminoplasty with manual reamers and/or a high-speed burr under direct endoscopic vision was performed to ensure the safety of the exiting nerve root during cage extraction. The retrieved cage was replaced with a large footprint, expandable titanium cage using the trans-Kambin approach. RESULTS: In all 3 cases, different types of interbody cages (1 titanium, 2 polyetheretherketone, and 1 expandable titanium cage) were removed under direct endoscopic view. In 1 case, we were only able to partially remove an impacted polyetheretherketone cage from the interbody disc endoscopically. The postoperative outcome significantly (P < 0.05) improved compared with preoperative scores in all 3 cases with a follow-up of 6 and 12 months, respectively. CONCLUSION: In most cases, lumbar interbody cages can be safely removed with endoscopic surgery with good preliminary clinical outcome. Nonetheless, further clinical research with long-term follow-up is required. CLINICAL RELEVANCE: Results indicate the feasibility of full-endoscopic removal of migrated and pseudoarthrotic lumbar interbody cages.

Thoracolumbar Interfascial Plane Block Results in Opioid-Free Postoperative Recovery After Percutaneous/Endoscopic Transforaminal Lumbar Interbody Fusion Surgery.

OBJECTIVE: To evaluate efficacy in reducing postoperative pain and opioid analgesia of a novel interdisciplinary strategy combining preoperative thoracolumbar interfascial plane (TLIP) block and percutaneous/endoscopic transforaminal lumbar interbody fusion surgery and to determine time to first postoperative ambulation and hospital length of stay. METHODS: In this retrospective review, 42 patients who underwent elective single-level percutaneous/endoscopic transforaminal lumbar interbody fusion surgery between 2015 and 2021 were divided into 2 groups: TLIP group with 17 patients who underwent TLIP block and non-TLIP group with 25 patients. Both groups received the same postoperative analgesia with morphine as patient-controlled rescue medication. Visual analog scale and Oswestry Disability Index scores were evaluated. Statistical evaluation was performed with Student t test. RESULTS: In contrast to the non-TLIP group, in the TLIP group, postoperative mean visual analog scale back score and mean Oswestry Disability Index score significantly decreased from 6.6 to 3.3 (P < 0.01) and 32.8 to 23.6 (P < 0.01), respectively, at hospital discharge. No differences were found between the groups at 1 month. Overall mean follow-up time was 29 ± 18 months (range, 3-78 months). Patients in the non-TLIP group were administered a median postoperative 24-hour morphine dose equivalent of 23 mg (range, 8-31 mg), while patients in the TLIP group did not require opioid analgesia (P < 0.01). Patients in the TLIP group started postoperative ambulation at a median of 4.1 hours (range, 2.5-26 hours) with a median hospital length of stay of 24 hours (range, 20-48 hours) (P = 0.112). CONCLUSIONS: TLIP block significantly improves patient outcome at hospital discharge after transforaminal lumbar interbody fusion surgery without postoperative administration of opioids. A prospective study is recommended to confirm our preliminary results.

Full Percutaneous Transforaminal Lumbar Interbody Fusion Using the Facet-sparing, Trans-Kambin Approach.

STUDY DESIGN: This was a prospective, multicenter, consecutive case series' study. OBJECTIVE: The objective of this study was to evaluate a novel facet-sparing, percutaneous transforaminal lumbar interbody fusion (pTLIF) technique consisting of percutaneous insertion of an expandable interbody cage through an endoscopic cannula with the trans-Kambin approach and complemented with percutaneous transpedicular screws and rods. SUMMARY OF BACKGROUND DATA: Lumbar interbody fusion by open or minimally invasive surgery is the usual treatment for degenerative disk disease but requires a relatively long recovery period. The transforaminal trans-Kambin approach is a standard in endoscopic spine surgery for safe intradiscal access without facet resection. METHODS: Preoperative and postoperative Visual Analogue Scale (VAS) and Oswestry Disability Index scores were quantitatively assessed at 1, 3, 6, and 12 months after surgery and then every 12 months for patients treated with pTLIF between 2009 and 2018 in 2 health care centers. An immediate postoperative control computed tomography scan was performed, whereas conventional postoperative x-ray controls were performed at 1 month and 1 year. Statistical evaluation was performed with the Student t test. RESULTS: A total of 51 patients (mean age, 59.3 y) were evaluated. The overall mean VAS score for axial lumbar pain improved from 6.6 to 1.8 (P<0.01), mean VAS score for leg pain from 5.5 to 1.2 (P<0.01), and mean Oswestry Disability Index scores from 30.3 to 11.8 (P<0.01) postoperatively with a mean follow-up of 27.9 months (range, 1-77.8 mo). Median estimated blood loss was 103.6 mL. Postoperative complications included 12 (22%) cases with transitory ipsilateral dysesthesia, 2 (4%) cases with transitory ipsilateral muscle weakness, and 3 (6%) clinically asymptomatic cases with radiologic cage subsidence. Median hospital stay was 1.4 days (range, 1-3.2 d). CONCLUSIONS: Postoperative scores for pTLIF significantly improved with minimal blood loss and no long-term complications. On the basis of this experience, the facet-sparing pTLIF is a reliable and safe technique with early hospital discharge, opening the way to outpatient instrumented spine surgery. LEVEL OF EVIDENCE: Level III.

Feasibility of Full Percutaneous Segmental Stabilization of the Lumbar Spine With a Combination of an Expandable Interbody Cage and an Interspinous Spacer: Preliminary Results.

INTRODUCTION: We evaluated the feasibility of a full percutaneous approach with an expandable interbody cage and an interspinous spacer for a segmental stabilization of the anterior and posterior columns of the lumbar spine, respectively, with local anesthesia. METHODS: Patients were prospectively included between 2012 and 2018 in this single-center, feasibility case series. An expandable interbody cage was inserted with endoscopy-based, facet-sparing percutaneous transforaminal lumbar interbody fusion (pTLIF). An interspinous spacer was percutaneously placed through the same skin incision. Pre- and postoperative Visual Analog Scale (VAS) and Oswestry Disability Index (ODI) outcomes at 1, 3, 6, 12, and 24 months were obtained and evaluated with the Student t test. Postoperative outcome was classified according to modified Macnab criteria. RESULTS: A total of 16 patients were included, presenting mean preoperative scores for VAS back of 6.9 ± 2.5, VAS leg 7.9 ± 1.2, and ODI 30.1 ± 4.5. Postoperative mean scores for VAS back of 1.9 ± 2.1, VAS leg 2.1 ± 3.4, and ODI 14.8 ± 13.0 significantly (P < .001) decreased with a mean follow-up of 18.1 ± 16.6 months (range 1-65.2). Postoperative outcome was excellent and good for 13 (81%) cases, fair for 2 (13%), and poor for 1 (6%) case with a preoperative spondylolisthesis, which required revision surgery due to persisting instability. Postoperative complications included 3 cases with transitory, ipsilateral dysesthesia and 2 cases with radiologic cage subsidence but no clinical symptoms. Median postoperative time until hospital discharge was 16 hours. CONCLUSION: Our preliminary results for this full percutaneous technique show a similar outcome compared to conventional surgery with a fast patient recovery and early postoperative hospital discharge, opening the way to instrumented, outpatient surgery.

Influence of Volatile Anesthesia on the Release of Glutamate and other Amino Acids in the Nucleus Accumbens in a Rat Model of Alcohol Withdrawal: A Pilot Study.

BACKGROUND: Alcohol withdrawal syndrome is a potentially life-threatening condition, which can occur when patients with alcohol use disorders undergo general anesthesia. Excitatory amino acids, such as glutamate, act as neurotransmitters and are known to play a key role in alcohol withdrawal syndrome. To understand this process better, we investigated the influence of isoflurane, sevoflurane, and desflurane anesthesia on the profile of excitatory and inhibitory amino acids in the nucleus accumbens (NAcc) of alcohol-withdrawn rats (AWR). METHODS: Eighty Wistar rats were randomized into two groups of 40, pair-fed with alcoholic or non-alcoholic nutrition. Nutrition was withdrawn and microdialysis was performed to measure the activity of amino acids in the NAcc. The onset time of the withdrawal syndrome was first determined in an experiment with 20 rats. Sixty rats then received isoflurane, sevoflurane, or desflurane anesthesia for three hours during the withdrawal period, followed by one hour of elimination. Amino acid concentrations were measured using chromatography and results were compared to baseline levels measured prior to induction of anesthesia. RESULTS: Glutamate release increased in the alcohol group at five hours after the last alcohol intake (p = 0.002). After 140 min, desflurane anesthesia led to a lower release of glutamate (p < 0.001) and aspartate (p = 0.0007) in AWR compared to controls. GABA release under and after desflurane anesthesia was also significantly lower in AWR than controls (p = 0.023). Over the course of isoflurane anesthesia, arginine release decreased in AWR compared to controls (p < 0.001), and aspartate release increased after induction relative to controls (p20min = 0.015 and p40min = 0.006). However, amino acid levels did not differ between the groups as a result of sevoflurane anesthesia. CONCLUSIONS: Each of three volatile anesthetics we studied showed different effects on excitatory and inhibitory amino acid concentrations. Under desflurane anesthesia, both glutamate and aspartate showed a tendency to be lower in AWR than controls over the whole timecourse. The inhibitory amino acid arginine increased in AWR compared to controls, whereas GABA levels decreased. However, there were no significant differences in amino acid concentrations under or after sevoflurane anesthesia. Under isoflurane, aspartate release increased in AWR following induction, and from 40 min to 140 min arginine release in controls was elevated. The precise mechanisms through which each of the volatile anesthetics affected amino acid concentrations are still unclear and further experimental research is required to draw reliable conclusions.

Percutaneous Transforaminal Lumbar Interbody Fusion (pTLIF) with a Posterolateral Approach for the Treatment of Denegerative Disk Disease: Feasibility and Preliminary Results.

BACKGROUND: Interbody fusion by open discectomy is the usual treatment for degenerative disk disease but requires a relatively long recovery period. The transforaminal posterolateral approach is a well-known standard in endoscopic spine surgery that allows direct access to the disk with progressive tissue dilation. The aim of this study was to assess the feasibility of percutaneous transforaminal interbody fusion (pTLIF) with insertion of an expandable or a standard rigid interbody implant for patients with degenerative disk disease with or without spondylolisthesis and for revision surgery. METHODS: Between 2009 and 2014, the pTLIF procedure was performed in 30 patients. Ten patients underwent insertion of a rigid implant (group A) and the remaining 20 underwent insertion of an expandable titanium interbody implant as the initial procedure (n = 10) (group B) or after failed back surgery (n = 10) (group C). Patient outcomes were scored with visual analogic scale (VAS), Oswestry disability index (ODI) and modified Macnab criteria. RESULTS: The mean follow-up period was 38 (17) (range 11 to 67) months. The outcome was excellent in 18, good in 10 and fair in 2. No poor results and no major complications were reported. No differences in VAS and ODI scores according to the study group were found. Median postoperative time until hospital discharge was 26 hours (20 to 68 hours). Postoperative values for VAS and ODI scores improved significantly (p<0.05) compared to preoperative data in all study groups. CONCLUSIONS: These preliminary results have shown the feasibility and efficacy of the pTLIF procedure using a posterolateral approach for the treatment of degenerative disk disease with or without spondylolisthesis up to grade 2 and in revision surgery. No significant differences in outcome were observed between an expandable and a rigid cage. Median postoperative time until hospital discharge was faster compared to standard TLIF (26 hours vs. 9.3 days).

L-dopa-induced dyskinesia: beyond an excessive dopamine tone in the striatum.

L-dopa remains the mainstay treatment for Parkinson's disease (PD), although in later stages, treatment is complicated by L-dopa-induced dyskinesias (LID). Current evidence links LID to excessive striatal L-dopa-derived dopamine (DA) release, while the possibility of a direct involvement of L-dopa itself in LID has been largely ignored. Here we show that L-dopa can alter basal ganglia activity and produce LID without enhancing striatal DA release in parkinsonian non-human primates. These data may have therapeutic implications for the management of advanced PD since they suggest that LID could result from diverse mechanisms of action of L-dopa.

Mapping brain regions in which deep brain stimulation affects schizophrenia-like behavior in two rat models of schizophrenia.

BACKGROUND AND OBJECTIVES: The development of more efficient treatment remains a major unmet need in the realm of schizophrenia disease. Using the maternal immune stimulation and the pubertal cannabinoid administration rat model of schizophrenia, the present study aimed at testing the hypothesis that deep brain stimulation (DBS) serves as a novel therapeutic technique for this disorder. METHODS: Adult offspring of dams, treated with the immune activating agent poly I:C (4 mg/kg, n = 50) or saline (n = 50), underwent bilateral stereotactic electrode implantation into one of the following brain regions: subthalamic nucleus (STN, n = 12/10), entopeduncularis nucleus (EP, n = 10/11), globus pallidus (GP, n = 10/10), medial prefrontal cortex (mPFC, n = 8/8), or dorsomedial thalamus (DM, n = 10/11). Adult rats treated with the CB1 receptor agonist WIN 55,212-2 (WIN, n = 16) or saline (n = 12) during puberty were bilaterally implanted with electrodes into either the mPFC (n = 8/6) or the DM (n = 8/6). After a post-operative recovery period of one week, all rats were tested on a well-established cross-species phenomenon that is disrupted in schizophrenia, the pre-pulse inhibition (PPI) of the acoustic startle reflex (ASR) under different DBS conditions. RESULTS: Poly I:C induced deficits in PPI of the ASR were normalized upon DBS. DBS effects depended on both stimulation target and stimulation parameters. Most prominent effects were found under DBS at high frequencies in the mPFC and DM. These effects were replicated in the pubertal WIN administration rat model of schizophrenia. CONCLUSIONS: Brain regions, in which DBS normalized PPI deficits, might be of therapeutic relevance to the treatment of schizophrenia. Results imply that DBS could be considered a plausible therapeutic technique in the realm of schizophrenia disease.

Usefulness of an expandable interbody spacer for the treatment of foraminal stenosis in extremely collapsed disks: preliminary clinical experience with endoscopic posterolateral transforaminal approach.

STUDY DESIGN: Clinical series of patients with degenerative disk disease undergoing an endoscopic posterolateral transforaminal procedure that used a reaming foraminoplasty technique to enlarge the foramen coupled with insertion of the B-Twin expandable spacer. OBJECTIVES: This retrospective analysis of 107 consecutive patients sought to assess the outcome of this surgical procedure. SUMMARY OF BACKGROUND DATA: Reamed endoscopic foraminoplasty under direct endoscopic vision has been shown to be suitable for extremely collapsed disks (>50% total disk height) despite the difficult access, especially at L5-S1. The authors tried to investigate the efficacy of an expandable spacer being inserted by the endoscopic transforaminal approach to solve foraminal stenosis without bone fusion techniques. METHODS: The procedure consists of bone reaming under direct endoscopic control to wide the foramen followed by insertion of the B-Twin expandable device as a disk spacer to restore partially or to maintain the height of the collapsed disk. Outcome measures included visual analog scale (VAS) for pain, the Oswestry Disability Index (ODI) for functional disability, and radioimaging studies. RESULTS: Mean follow-up was 27.2 months. Clinical outcome was considered excellent in 64 patients, good in 25, fair in 10, and poor in 8. Results were similar in single and double B-Twin spacer insertions. Postoperative mean values for VAS and ODI scores improved significantly as compared with preoperative data. Mean VAS and ODI scores were significantly higher in patients with fair or poor results than in those with excellent or good outcome. In 2 cases, clear signs of end plate bone resorption in the control computed tomographic scans at 6 months and 12 months leading to a substantial loss of disk height were documented. CONCLUSIONS: This preliminary study has shown the efficacy of an endoscopic surgical technique for the treatment of foraminal stenosis in extremely collapsed disks.

Activity modulation of the globus pallidus and the nucleus entopeduncularis affects compulsive checking in rats.

Deep brain stimulation at high frequencies (HFS) is currently studied in the treatment of therapy-refractory obsessive-compulsive disorder (OCD). The diversity of targeted brain areas and the discrepancy in demonstrating beneficial effects, highlight the need for better mapping of brain regions in which HFS may yield anti-compulsive effects. This goal may be achieved by investigating the effects of HFS in appropriate animal models of OCD. The present study tested the effect of bilateral HFS or pharmacological inactivation (as induced by intracerebral administration of the GABA-agonist muscimol) of both the Globus pallidus (GP; rodent equivalent to human GP externus) and the Nucleus entopeduncularis (EP; rodent equivalent to human GP internus) on checking behaviour in the quinpirole rat model of OCD. We demonstrate that HFS of the GP does not and HFS of the EP only partially reduces OCD-like behaviour in rats. In contrast, pharmacological inactivation of both GP and EP significantly reduces OCD-like behaviour in the model. These data contrast previously derived data on the effectiveness of HFS of the subthalamic nucleus, nucleus accumbens, GP and EP in the same and other rat models of OCD. We conclude that (i) although GP and EP play an important role in the pathophysiology of OCD, these areas may not represent first choice target structures for HFS, (ii) the effectiveness of HFS may depend on different subtypes of OCD, represented in different animal models, and (iii) differential net mechanisms may subserve the effectiveness of HFS and pharmacological inactivation.

Development of an implantable microstimulation system for chronic DBS in rodents.

High frequency deep brain stimulation (DBS) of certain basal ganglia nuclei (e.g. subthalamic nucleus, STN) has emerged as a powerful neuromodulatory approach in the treatment of late stage Parkinson's disease patients. However, the underlying mechanisms of action are not fully understood. We have therefore established an implantable DBS device for small laboratory animals (e.g. rats) that allows the reliable and safe application of continuous DBS for at least 3 weeks. We could further show that miniaturized monopolar electrodes comprising activated iridium are suitable for continuous stimulation of small brain structures like the STN without inducing severe insertion or stimulation related injuries.

High-frequency stimulation of the nucleus accumbens core and shell reduces quinpirole-induced compulsive checking in rats.

Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy-refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti-compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD-like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole-induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.

Pattern of long-term sensorimotor recovery following intrastriatal and--accumbens DA micrografts in a rat model of Parkinson's disease.

The functional restorative capacity of fetal dopaminergic (DA) transplants is governed by a number of critical parameters including graft location, survival of DA neurons, and transplantation technique. In addition, there is an ongoing controversy whether "too much" or "too little" survival of DA neurons is responsible for the incomplete functional recovery observed in some transplanted Parkinson's disease (PD) patients. Here we investigated two implantation sites, the nucleus accumbens (NAc) and the caudate-putamen unit (CPU), and two different graft distributions within the CPU, i.e., two 0.75 microL deposits (CPU-2) versus six 0.25 microL deposits (CPU-6) in a rat model of PD. Grafts were derived from E14 rat ventral mesencephalon and the long-term functional outcome was evaluated with a wide range of complex-sensorimotor behavioral tests. The data show that forelimb stepping, balancing behavior, and skilled forelimb reaching behavior was more restored in CPU-6-grafted animals as compared to CPU-2 animals, although the number surviving dopaminergic neurons and dopamine release were similar in the two groups. Furthermore, a correlation analysis revealed a number of inverse relationships between the rate of DA neuron survival and sensorimotor performances, e.g., for skilled forelimb use. DA grafts placed into the NAc induced a partial recovery in drug-induced rotation tests but failed to restore any of the other sensorimotor behaviors tested. Taken together, these data have important implications both for a better understanding of the complex functional graft-host interactions as well as for the further optimization of clinical neural transplantation strategies in neurodegenerative diseases.

Prenatal immune activation leads to multiple changes in basal neurotransmitter levels in the adult brain: implications for brain disorders of neurodevelopmental origin such as schizophrenia.

Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers by high-performance liquid chromatography on post-mortem tissue. We found that prenatal immune activation significantly increased the levels of dopamine and its major metabolites in the lateral globus pallidus and prefrontal cortex, whilst at the same time it decreased serotonin and its metabolite in the hippocampus, nucleus accumbens and lateral globus pallidus. In addition, a specific reduction of the inhibitory amino acid taurine in the hippocampus was noted in prenatally PolyI:C-exposed offspring relative to controls, whereas central glutamate and gamma-aminobutyric acid (GABA) content was largely unaffected by prenatal immune activation. Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism to the emergence of neurochemical imbalances in adulthood, which may be critically involved in the precipitation of adult behavioural and pharmacological abnormalities after prenatal immune challenge.

Phenotypic differences in behavior, physiology and neurochemistry between rats selected for tameness and for defensive aggression towards humans.

To better understand the biology of tameness, i.e. tolerance of human presence and handling, we analyzed two lines of wild-derived rats (Rattus norvegicus) artificially selected for tameness and defensive aggression towards humans. In response to a gloved human hand, tame rats tolerated handling, whereas aggressive rats attacked. Cross-fostering showed that these behavioral differences are not caused by postnatal maternal effects. Tame rats were more active and explorative and exhibited fewer anxiety-related behaviors. They also had smaller adrenal glands, larger spleens and lower levels of serum corticosterone. Blood glucose levels were lower in tame rats, whereas the concentrations of nine amino acids were higher. In the brain, tame rats had lower serotonin and higher taurine levels than aggressive rats. Our findings reinforce the notion that tameness is correlated with differences in stress response and will facilitate future efforts to uncover the genetic basis for animal tameness.

Subthalamic stimulation increases striatal tyrosine hydroxylase phosphorylation.

Subthalamic stimulation enhances striatal tyrosine hydroxylase activity, which is regulated by phosphorylation at different serine residues. Western blotting was performed to investigate phosphorylation at the serine residues 19, 31 and 40 in striatal tissue of rats that had received subthalamic stimulation or sham stimulation for 2 h. In animals that were killed directly after stimulation, the tyrosine hydroxylase protein content was unchanged, whereas phosphorylation at the serine residue 19 was increased and phosphorylation at the serine residues 31 and 40 tended to be higher compared with controls. By contrast, tyrosine hydroxylase protein content and phosphorylation were similar in rats that were killed 24 h after stimulation. Our results suggest that subthalamic stimulation may increase tyrosine hydroxylase activity via increased phosphorylation.

Continuous high-frequency stimulation in freely moving rats: development of an implantable microstimulation system.

High-frequency stimulation (HFS) of basal ganglia and thalamic nuclei is an established treatment for various movement disorders and has recently been extended to other neuro-psychiatric conditions. Numerous experimental studies in small laboratory animals provided important insights in the mode of action of HFS. However, the interpretation of the results is often limited by the use of short-term HFS, while patients receive continuous stimulation for many years. One reason is the lack of an established model for the application of long-term HFS in small animals. Therefore, we thought to develop an implantable microstimulation system for small laboratory animals and to establish a protocol for long-term HFS by defining non-damaging stimulus parameters with respect to brain integrity. For this purpose, we designed a miniaturized, microcontroller-based, and programmable microstimulator that allows the reliable application of continuous HFS for up to 5 weeks. Chronic HFS (total stimulation time: 3 weeks) of the subthalamic nucleus with up to 100 microA (5.2 nC/phase) through monopolar electrodes comprising activated iridium did not induce significant tissue damage as assessed by various histological techniques (Nissl's, hematoxylin and eosin, Klüver-Barrera, van Gieson's staining, NeuN and GFAP-immunoreactivity). In conclusion, chronic HFS with an implantable stimulator can be successfully applied in small animals.

High frequency stimulation of the subthalamic nucleus modulates neurotransmission in limbic brain regions of the rat.

Despite the benefit high frequency stimulation (HFS) of the subthalamic nucleus (STN) has on motor symptoms of Parkinson's Disease (PD), accumulating data also suggest effects of STN-HFS on non-motor behavior. This may be related to the involvement of the STN in the limbic basal ganglia-thalamocortical loops. In the present study we investigated the effect of acute STN-HFS on neurotransmission in associated structures of these pathways, i.e. the nucleus accumbens (NAc) core and shell as well as the ventral tegmental area (VTA) using in vivo microdialysis. Experiments were performed in anaesthetized naive rats and rats selectively lesioned in the substantia nigra pars compacta (SNc) or VTA. We demonstrate that: 1. STN-HFS leads to an increase in DA in the NAc, 2., these effects are more pronounced in the NAc shell than in the NAc core, 3. STN-HFS leads to a decrease in GABA in the VTA, 4. preceding lesion of the SNc does not seem to affect the effect of STN-HFS on accumbal DA transmission whereas 5. preceding lesion of the VTA seems to prohibit further detection of DA in the NAc. We conclude that STN-HFS significantly affects neurotransmission in the limbic system, which might contribute to explain the non-motor effects of STN-HFS.

Unilateral lesion of the subthalamic nucleus transiently provokes bilateral subacute glial cell proliferation in the adult rat substantia nigra.

Ablative or functional lesions of the subthalamic nucleus (STN) lead to significant improvements of motor deficits and major levodopa associated motor complications in patients with Parkinson's disease. The biological mechanisms underlying the clinical effectiveness still remain largely unknown. It has been demonstrated previously that the adult substantia nigra (SN) bears the capacity for cellular plasticity throughout adulthood and that this property can be influenced by external stimuli. In the present study we investigated the subacute and chronic effects of unilateral STN-lesion on newly generated neural cells in the adult healthy SN of the rat. With this experimental design we demonstrate a bilateral transient increase in the total numbers of newborn nigral cells following STN-lesion. Additionally, we show a transient bilateral decrease in the number of newborn neuro-glial antigen 2 (NG2)-positive and in the number of new microglia cells. No newborn neurons, however, were detected. Thus, we conclude that unilateral ablative STN lesion transiently changes plasticity of neural cell subpopulations in the healthy adult SN of the rat.

Placebo-controlled chronic high-frequency stimulation of the subthalamic nucleus preserves dopaminergic nigral neurons in a rat model of progressive Parkinsonism.

Chronic high-frequency stimulation (HFS) of the subthalamic nucleus (STN) protects nigral dopaminergic neurons from neurodegeneration in animal models of Parkinson's disease (PD). However, these data are challenged by the lack of control for neuroprotective effects that might be related to tissue damage due to electrode insertion or STN-HFS. Here we report the first placebo-controlled study on continuous STN-HFS in a rat model of PD using an implantable microstimulation system. We found a significant increase of preserved dopaminergic nigral neurons on the lesioned side (expressed as ratio to the non-lesioned side) of approximately 50% in comparison to STN sham-stimulated and STN-naive rats. These data provide evidence for the phenotypic rescue of nigral dopamine neurons by long-term STN-HFS in this animal model of PD.