Alternating verbal fluency performance following bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease.

BACKGROUND AND PURPOSE: Despite common occurrences of verbal fluency declines following bilateral subthalamic nucleus deep brain stimulation (STN-DBS) for the treatment of Parkinson's disease (PD), alternating fluency measures using cued and uncued paradigms have not been evaluated. METHODS: Twenty-three STN-DBS patients were compared with 20 non-surgical PD patients on a comprehensive neuropsychological assessment, including cued and uncued intradimensional (phonemic/phonemic and semantic/semantic) and extradimensional (phonemic/semantic) alternating fluency measures at baseline and 6-month follow-up. RESULTS: STN-DBS patients demonstrated a greater decline on the cued phonemic/phonemic fluency and the uncued phonemic/semantic fluency tasks compared to the PD patients. For STN-DBS patients, verbal learning and information processing speed accounted for a significant proportion of the variance in declines in alternating phonemic/phonemic and phonemic/semantic fluency scores, respectively, whilst only naming was related to uncued phonemic/semantic performance for the PD patients. Both groups were aided by cueing for the extradimensional task at baseline and follow-up, and the PD patients were also aided by cueing for the phonemic/phonemic task on follow-up. CONCLUSIONS: These findings suggest that changes in alternating fluency are not related to disease progression alone as STN-DBS patients demonstrated greater declines over time than the PD patients, and this change was related to declines in information processing speed.

Alleviation of drenching sweats following subthalamic deep brain stimulation in a patient with Parkinson's disease--a case report.

We report a patient with Parkinson's disease whose whole body drenching sweats were completely alleviated by stimulation of the subthalamic nucleus and/or adjacent structures. Sweating reappeared 4h after the pulse generator (stimulation) was turned off and ceased when stimulation was resumed. Imaging studies with reconstruction indicated that stimulation of, or spread of stimulation from, the caudal medial aspect of the right subthalamic nucleus and/or the caudal aspect of the ventral thalamus/zona incerta may be responsible for alleviating the drenching sweats.

Vagus nerve stimulation for essential tremor: a pilot efficacy and safety trial.

OBJECTIVE: To assess the safety and efficacy of vagus nerve stimulation (VNS) for essential tremor (ET). METHODS: This was a pilot open-treatment trial at three centers, with masked videotape tremor assessments. Inclusion required a severity score of 3 or 4 on the Tremor Rating Scale (TRS) in one or both hands. At baseline, tremor was assessed with TRS and Unified Tremor Rating Assessment (UTRA), accelerometry, and a videotape protocol. The VNS device was implanted with leads placed around the left cervical vagus nerve. Stimulation was adjusted over 4 weeks before the repeat tremor assessments. Two raters masked to the study visit scored the videotapes. RESULTS: Nine subjects participated, with a mean age of 65 years and a mean age at onset of tremor of 24. Investigators rated hand tremor as mildly improved (TRS 2.3 +/- 0.7 during VNS vs 3.0 +/- 0.4 during baseline, p = 0.06). Accelerometry-measured total power improved 50.2 +/- 31.8% (p < 0.01). Videotape tremor scores were highly correlated between the masked raters and revealed no changes in tremor scores with treatment. VNS was well tolerated, with the most common adverse events being stimulation related. CONCLUSIONS: VNS was judged by investigators to mildly improve upper extremity tremor. This finding was not confirmed in videotape scoring by masked raters. VNS is not likely to have a clinically meaningful effect on ET.

Randomized, double-blind trial of glial cell line-derived neurotrophic factor (GDNF) in PD.

OBJECTIVE: To assess the safety, tolerability, and biological activity of glial cell line-derived neurotrophic factor (GDNF) administered by an implanted intracerebroventricular (ICV) catheter and access port in advanced PD. BACKGROUND: GDNF is a peptide that promotes survival of dopamine neurons. It improved 6-OHDA- or MPTP-induced behavioral deficits in rodents and monkeys. METHODS: A multicenter, randomized, double-blind, placebo-controlled, sequential cohort study compared the effects of monthly ICV administration of placebo and 25, 75, 150, 300, and 500 to 4,000 microg of GDNF in 50 subjects with PD for 8 months. An open-label study extended exposure up to an additional 20 months and maximum single doses of up to 4,000 microg in 16 subjects. Laboratory testing, adverse events (AE), and Unified Parkinson's Disease Rating Scale (UPDRS) scoring were obtained at 1- to 4-week intervals throughout the studies. RESULTS: Twelve subjects received placebo and seven or eight subjects were assigned to each of the other GDNF dose groups. "On" and "off" total and motor UPDRS scores were not improved by GDNF at any dose. Nausea, anorexia, and vomiting were common hours to several days after injections of GDNF. Weight loss occurred in the majority of subjects receiving 75 microg or larger doses of GDNF. Paresthesias, often described as electric shocks (Lhermitte sign), were common in GDNF-treated subjects, were not dose related, and resolved on discontinuation of GDNF. Asymptomatic hyponatremia occurred in over half of subjects receiving 75 microg or larger doses of GDNF; it was symptomatic in several subjects. The open-label extension study had similar AE and lack of therapeutic efficacy. CONCLUSIONS: GDNF administered by ICV injection is biologically active as evidenced by the spectrum of AE encountered in this study. GDNF did not improve parkinsonism, possibly because GDNF did not reach the target tissues--putamen and substantia nigra.

Thalamic deep brain stimulation: effects on the nontarget limbs.

Unilateral thalamic ventral intermediate (VIM) deep brain stimulation (DBS) is now accepted as an effective treatment for essential tremor (ET) and tremor related to Parkinson's disease (PD). The effects of unilateral placement on the side ipsilateral to the surgical site have not been carefully evaluated. To systematically assess the effects ipsilateral to the surgical side and to determine the effects of device inactivation on the baseline tremor, we evaluated tremor in 73 patients approximately 3 months after their unilateral thalamic placement. Assessment included blinded and unblinded ratings using the Unified Parkinson's Disease Rating Scale for PD patients and a modified Tremor Rating Scale in ET patients. All measures of tremor contralateral to the implantation site improved significantly and robustly in both PD and ET. Implantation did not worsen tremor by any measure on the ipsilateral side. There was mild ipsilateral improvement as measured by lower observed tremor scores in ET (6.0 +/- 1.8 to 5.0 +/- 1.9, P < 0.005), but not PD. There was no rebound augmentation of tremor in either hand after the devices were deactivated in either group. We conclude that VIM DBS may mildly improve ipsilateral ET, and that concerns about meaningful ipsilateral tremor augmentation after device deactivation are not warranted.

Vagus nerve stimulation (VNS) for treatment-resistant depression: efficacy, side effects, and predictors of outcome.

This open pilot study of vagus nerve stimulation (VNS) in 60 patients with treatment-resistant major depressive episodes (MDEs) aimed to: 1) define the response rate; 2) determine the profile of side effects; and, most importantly; 3) establish predictors of clinical outcome. Participants were outpatients with nonatypical, nonpsychotic, major depressive or bipolar disorder who had not responded to at least two medication trials from different antidepressant classes in the current MDE. While on stable medication regimens, the patients completed a baseline period followed by device implantation. A 2-week, single blind, recovery period (no stimulation) was followed by 10 weeks of VNS. Of 59 completers (one patient improved during the recovery period), the response rate was 30.5% for the primary HRSD(28) measure, 34.0% for the Montgomery-Asberg Depression Rating Scale (MADRAS), and 37.3% for the Clinical Global Impression-Improvement Score (CGI-I of 1 or 2). The most common side effect was voice alteration or hoarseness, 55.0% (33/60), which was generally mild and related to output current intensity. History of treatment resistance was predictive of VNS outcome. Patients who had never received ECT (lifetime) were 3.9 times more likely to respond. Of the 13 patients who had not responded to more than seven adequate antidepressant trials in the current MDE, none responded, compared to 39.1% of the remaining 46 patients (p =.0057). Thus, VNS appears to be most effective in patients with low to moderate, but not extreme, antidepressant resistance. Evidence concerning VNS' long-term therapeutic benefits and tolerability will be critical in determining its role in treatment-resistant depression.

Concepts and methods in chronic thalamic stimulation for treatment of tremor: technique and application.

OBJECTIVE: To rationalize the technique and reduce the costs associated with chronic deep brain stimulation of the thalamus for treatment of refractory tremor. METHODS: The efficacy and safety of a modification in surgical techniques was prospectively assessed in 94 patients with tremor. Bilateral electrodes were implanted in 29 patients, and 65 patients received unilateral implants. Forty-five patients had Parkinson's disease tremor, 42 patients had essential tremor, and 7 patients had kinetic tremors of different causes. In all instances, intraoperative stimulations to analyze the thresholds of intrinsic and extrinsic responses were performed directly with the implanted leads. The electrodes were repositioned until satisfactory results were achieved. The pulse generators were implanted directly after the first step in the same operative session. Patients were not subjected to interoperative test stimulation trials. RESULTS: Postoperative improvement of tremor at a mean follow-up of 11.9 months was rated as excellent in 47 patients (50%), marked in 37 patients (39%), moderate in 8 patients (9%), and minor in 2 patients (2%). There was no persistent morbidity related to surgery. In patients with Parkinson's disease, the symptomatic improvement of tremor was rated as excellent in 51% of patients, marked in 36%, moderate in 11%, and minor in 2%. In patients with essential tremor, symptomatic outcome was classified as excellent in 57% of patients, marked in 36%, moderate in 5%, and minor in 2%. Six of the seven patients with kinetic tremor achieved marked symptomatic improvement, and one patient experienced moderate improvement. Forty patients experienced stimulation-related side effects. Side effects were mild in general, and they were reversible with a change in electrical parameters. They occurred more frequently in patients who had bilateral stimulation. CONCLUSION: Excellent to marked improvement of tremor is achieved in the majority of patients with physiological target determination via implanted leads in thalamic deep brain stimulation. Interoperative test stimulation trials are unnecessary. Modifications in technique may help to reduce the costs of the related hospital stay.

Thalamic deep brain stimulation: comparison between unilateral and bilateral placement.

BACKGROUND: Unilateral thalamic deep brain stimulation (DBS) is accepted as an effective treatment for essential tremor (ET) and the tremor of Parkinson disease (PD). There are, however, relatively little data concerning bilateral thalamic DBS and no thorough comparisons between the 2 methods. METHODS: To assess the relative benefit of a staged second contralateral DBS placement in patients with PD and ET, we compared preoperative baseline assessments with those at 3 months after the initial implantation, and again at 3 months after the second contralateral implantation. The assessments included the Unified Parkinson's Disease Rating Scale for patients with PD (n = 8) and a modified Unified Tremor Rating Assessment for patients with ET (n = 13). The design included open and blinded (unknown activation status) assessments. RESULTS: Overall, after the second implantation, all specific measures assessing tremor contralateral to that side improved in patients with PD and ET, generally without sacrificing those contralateral to the first side implantation. Midline tremors (face and head) improved only after the second side implantation. In patients with ET, functional and subjective scores tended to further improve after the second placement; however, patients with PD had less subjective improvement. Hand tremor scores in patients with ET randomized to "on" stimulation improved from 6.7 +/- 0.9 to 1.3 +/- 1.2 (P<.005). The scores of patients with PD randomized to on stimulation improved from 9.3 +/- 1.0 to 1.0 +/- 0.5. (Data are given as mean +/- SD.) Tremor scores did not change from baseline in those patients randomized to "off" stimulation in either group. Adverse events related to stimulation increased after the second implantation in both groups. CONCLUSIONS: Bilateral thalamic DBS is more effective than unilateral DBS at controlling bilateral appendicular and midline tremors of ET and PD. Despite this, overall functional disability only improved in patients with ET, possibly secondary to more problematic adverse events in patients with PD, especially balance problems. Bilateral DBS should be considered when unilateral DBS does not offer satisfactory benefit, especially in patients with ET.

Mechanism of action of pulsed high electric field (PHEF) on the membranes of food-poisoning bacteria is an 'all-or-nothing' effect.

Salmonella typhimurium (CRA 1005) was more sensitive than Listeria monocytogenes (NCTC 11994) to pulsed high electric field (PHEF) treatment in distilled water (10, 15 and 20 kV/cm), 10 mM tris-maleate buffer pH 7.4 (15 kV/cm) and model beef broth (0.75% w/v: 15 kV/cm). Sublethal injury could not be detected using a selective medium plating technique, indicating that bacterial inactivation by PHEF may be an 'all-or-nothing' event. PHEF-induced membrane permeabilization resulted in increased UV-leakage and a decreased ability of L. monocytogenes to maintain a pH gradient.

Long-term intrathecal administration of glycine prevents mechanical hyperalgesia in a rat model of neuropathic pain.

Neuropathic pain has been postulated to be mediated, in part, by amino acid neurotransmitters including glycine. The current study examined the effects of continuous intrathecal glycine administration (0.1 mumol 0.5 microliter-1 h-1) on the development of mechanical hyperalgesia and other features of neuropathic pain evoked by unilateral loose ligation of the sciatic nerve in the rat. Each hind paw was tested for withdrawal threshold to mechanical stimuli prior to, and after ligation at intervals of 3, 6, 9, 12 and 16 days. Pain behavior (posture and gait) and hind paw dystrophic features (redness and swelling) were also examined. Glycine increased the normal mechano-nociceptive responses and prevented the development of mechano-nociceptive hyperalgesia. Spontaneous nociceptive behavior and hind paw dystrophic features, seen in the saline treated rats, were significantly diminished. Our results suggest that spinal cord inhibitory glycinergic activity is important for normal mechano-receptive responsitivity and development of mechano-nociceptive hyperalgesia in this model.

Vagus nerve stimulation (VNS) for treatment-resistant depressions: a multicenter study.

BACKGROUND: Vagus Nerve Stimulation (VNS) delivered by the NeuroCybernetic Prosthesis (NCP) System was examined for its potential antidepressant effects. METHODS: Adult outpatients (n = 30) with nonpsychotic, treatment-resistant major depressive (n = 21) or bipolar I (n = 4) or II (n = 5; depressed phase) disorders who had failed at least two robust medication trials in the current major depressive episode (MDE) while on stable medication regimens completed a baseline period followed by NCP System implantation. A 2-week, single-blind recovery period (no stimulation) was followed by 10 weeks of VNS. RESULTS: In the current MDE (median length = 4.7 years), patients had not adequately responded to two (n = 9), three (n = 2), four (n = 6), or five or more (n = 13) robust antidepressant medication trials or electroconvulsive therapy (n = 17). Baseline 28-item Hamilton Depression Rating Scale (HDRS(28)) scores averaged 38.0. Response rates (> or =50% reduction in baseline scores) were 40% for both the HDRS(28) and the Clinical Global Impressions-Improvement index (score of 1 or 2) and 50% for the Montgomery-Asberg Depression Rating Scale. Symptomatic responses (accompanied by substantial functional improvement) have been largely sustained during long-term follow-up to date. CONCLUSIONS: These open trial results suggest that VNS has antidepressant effects in treatment-resistant depressions.

Treatment of chronic pain in failed back surgery patients with spinal cord stimulation: a review of current literature and proposal for future investigation.

Objective. The authors attempted to design and conduct a randomized, prospective study to investigate the efficacy of spinal cord stimulation (SCS) for patients with chronic back and leg pain following at least one previous surgery. While the scientific advantages of the randomized, prospective trial are considerable, the authors encountered numerous practical and ethical difficulties with conducting these trials. These are reviewed and an alternative investigative technique proposed. Materials and Methods. The literature on interventional and minimally invasive treatments for this population group is reviewed, and the strengths and weaknesses of different methodologies for conducting clinical research in an interventional setting are examined. Results. The difficulties inherent in a randomized, prospective study for an intervention vs. a nonintervention group are addressed, and an alternative methodology is proposed-that of a randomized interventional design. In this design, patients are assigned to a given treatment group, with each treatment exclusively available at different centers. Conclusions. By utilizing a randomized interventional study design, problems of comparability of procedures, provider reluctance to participate in randomized clinical trials, provider bias, detection bias, and transfer bias are eliminated. It is suggested that future investigations, particularly those which are interventionally or device-based, conform to this particular model.

Intrathecal treatment with MK-801 suppresses thermal nociceptive responses and prevents c-fos immunoreactivity induced in rat lumbar spinal cord neurons.

Sensitization of the second order neurons in the spinal dorsal horn after somatic noxious stimuli is partly mediated by the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor. These neurons also express c-Fos immunoreactivity in response to the somatic noxious stimuli. The present study assessed the influence of intrathecal pre-treatment with MK-801, a non-competitive antagonist of NMDA receptor, on thermal sensitization following peripheral noxious heat stimulation. In addition, the influence of MK-801 on c-Fos immunoreactivity in the rat lumbar spinal cord neurons after the peripheral noxious heat was examined. Sprague-Dawley rats were subject to intrathecal catheterization and administration of MK-801 or saline before and after noxious heat (52 degrees C) stimulation of rat hindpaws. Thermal sensitization was tested after MK-801 (0.1 mumol 10 microliters-1). Fos-like immunoreactivity was evaluated 2 h after noxious stimulation in a separate group of animals. MK-801 significantly increased the thermal withdrawal threshold by 60% following noxious heat stimulation and reduced c-Fos immunoreactivity in the second order neurons by 70% in the dorsal horn. The study suggests that glutamate plays a pivotal role in the thermal nociceptive pathway and indicates that the NMDA receptor is necessary to maintain normal thermal sensitization, possibly by regulating c-fos gene expression in second order neurons.

Ketamine suppresses c-fos expression in dorsal horn neurons after acute constrictive sciatic nerve injury in the rat.

Fos immunoreactivity within the spinal cord in a model of neuropathic pain was studied. Dorsal horn neurons in laminae I and II exhibited selective expression within the tibial, peroneal and posterior cutaneous nerve territories which, in turn, was suppressed during ketamine but not halothane anesthesia. Fos immunoreactive neurons have a unique response pattern to neuropathic pain which is sensitive to ketamine.

Pulsed high electric field causes 'all or nothing' membrane damage in Listeria monocytogenes and Salmonella typhimurium, but membrane H+-ATPase is not a primary target.

Salmonella typhimurium (CRA 1005) was more sensitive than Listeria monocytogenes (NCTC 11994) to pulsed high electric field (PHEF) treatment in distilled water (10, 15 and 20 kV/cm), 10 mM Tris-maleate buffer, pH 7.4 (15 kV/cm) and model beef broth (0.75%, w/v; 15 kV/cm). Sublethal injury could not be detected using a selective medium plating technique, indicating that bacterial inactivation by PHEF may be an 'all or nothing' event. PHEF-induced membrane permeabilisation resulted in an increase in the leakage of UV-absorbing material from the bacteria (UV-leakage) and a decreased ability of L. monocytogenes to maintain a pH gradient. A lack of correlation between the inhibition of H+-ATPase activity and PHEF treatment, cell viability or UV-leakage indicates that this enzyme is probably not a primary site of bacterial inactivation despite its role in the maintenance of internal pH.

Antisense of c-fos gene attenuates Fos expression in the spinal cord induced by unilateral constriction of the sciatic nerve in the rat.

Sciatic nerve constriction induces expression of c-fos protein in dorsal horn neurons of the spinal cord. Intrathecal administration of c-fos antisense (30 nmol/20 microl) into the lumbar region (L1-L5) 18 h prior to nerve ligation attenuated 80% of Fos-immunoreactivity 90 min after ligation compared to rats infused with c-fos sense or saline. Thus, c-fos antisense may be a useful tool in assessing the role of the c-fos gene in an animal model of neuropathic pain.

Noxious thermal stimulation of c-fos activity induced in rat lumbar spinal cord is reduced by AP-5 but not by glycine.

The effects of intrathecal administration of NMDA (N-methyl-D-aspartic acid) receptor antagonist AP-5 (2-Amino-5-phosphonopentanoic acid), a competitive and specific NMDA antagonist, and glycine on the neuronal expression of c-fos protein (Fos) in the dorsal neurons lumbar segments four and five were studied after noxious heat stimulation. Heat (52 degrees C, 3 s per application, repeated 10 times) was applied to the hindpaws of rats. NMDA receptor antagonist AP-5 (0.1 mmol/10 ml, i.t.) suppressed the noxious heat-induced Fos immunoreactivity by 65% as compared to animals pre-treated with saline. In contrast, glycine (0.1 micromol/10 microl, it.) did not influence Fos expression induced by the noxious heat stimulation. This study suggests that excitatory amino acids, e.g. glutamate but not the inhibitory aminos acid, glycine, plays a role in thermal nociception which in turn is mediated, in part, by c-fos activity.

Unilateral thalamic deep brain stimulation for refractory essential tremor and Parkinson's disease tremor.

OBJECTIVE: To determine the efficacy and tolerability of unilateral thalamic deep brain stimulation (DBS) for patients with medically refractory essential tremor (ET) and the tremor associated with Parkinson's disease (PD). BACKGROUND: The tremor of ET and PD may produce functional disability despite optimal medical therapy. Several reports have demonstrated efficacy of thalamic DBS in this scenario. METHODS: Preoperative and 3-month postoperative tremor ratings were compared in 33 patients (14 ET and 19 PD) with severe tremor. Evaluations included Unified Parkinson's Disease Rating Scale (UPDRS) scores for PD patients and a modified Unified Tremor Rating Scale in ET patients. Open-label and blinded data (unknown activation status) were obtained. RESULTS: ET patients demonstrated an 83% reduction (p < 0.0001) in observed contralateral arm tremor. All measures of tremor including writing samples, pouring tests, subjective functional surveys, and disability scores improved significantly. PD patients demonstrated an 82% reduction (p < 0.0001) in contralateral tremor and significant improvement in disability and global impressions. There was, however, no meaningful improvement in other motor aspects of the disease, and the total UPDRS part II (activities of daily living) score did not change. Adverse events, more common in ET patients, were generally mild and were usually eliminated by adjustment of the device parameters. CONCLUSIONS: Thalamic DBS is a safe and effective treatment of ET and the tremor of PD. In PD, its use should be limited to patients in whom high-amplitude tremor results directly in significant functional disability.

Glycine receptor reduction within segmental gray matter in a rat model in neuropathic pain.

Glycine is an amino acid neurotransmitter found in the spinal cord and is closely associated with interneurons that modulate afferent activity. We have previously shown that low segmental glycine concentrations or blockade of normal glycinergic activity lowers the threshold for pain thresholds. In addition, intrathecal glycine infusion increases the pain threshold in animal models of neuropathic pain. However, the role of the glycine receptor in neuropathic pain is not clear and is the basis for the current study. Using a unilateral sciatic nerve constriction injury model of neuropathic pain, the strychnine sensitive glycine receptor population was studied using immunohistochemical techniques. Glycine receptors are reduced in number in the dorsal horn bilaterally in injured animals. Glycine and related compounds are potentially valuable agents for treating chronic pain conditions in humans. A better understanding of glycine-receptor interactions should prove valuable as these compounds are studied in greater depth.

Transdermal fentanyl as treatment for chronic low back pain.

Management of chronic low back pain often includes oral opioid use. The effectiveness of therapy is dependent upon compliance, which in turn is dependent upon response, side effects, access, and convenience. Our hypothesis was that a transdermal fentanyl system would provide more effective pain management than oral opioids. Fifty patients with chronic low back pain were examined. After litration to levels corresponding to current oral opioid use, each patient was maintained on transdermal fentanyl for one month. Oral opioid therapy was then resumed. Their experience was assessed with the a visual analogue scale for pain intensity, a numerical pain score, the Oswestry disability questionnaire, the pain disability index, and the Verran Snyder-Halpern sleep scale. Significant improvement in pain relief and disability was found with transdermal fentanyl compared with oral opioids. Mild opioid side effects were common, but easily controlled. Use of transdermal fentanyl is an effective alternative to oral opioids for managing chronic low back pain.