Nonlinear Terahertz Polarizability of Electrons Solvated in a Polar Liquid.

The nonlinear polaronic response of electrons solvated in liquid 2-propanol is studied by two-dimensional terahertz spectroscopy. Solvated electrons with a concentration of c_{e}≈800 µM are generated by femtosecond photoionization of alcohol molecules. Electron relaxation to a localized ground state impulsively excites coherent polaron oscillations with a frequency of 3.9 THz. Off-resonant perturbation of the terahertz coherence by a pulse centered at 1.5 THz modifies the polaron oscillation phase. This nonlinear change of electron polarizability is reproduced by theoretical calculations.

Spatial distribution of electric-field enhancement across the gap of terahertz bow-tie antennas.

The electric-field enhancement in terahertz (THz) antennas designed for nonlinear THz spectroscopy of soft matter is characterized by spatially resolved electrooptic sampling. To mimic the relevant interaction geometry, metallic, resonant bow-tie antennas are deposited on a thin zinc telluride crystal of 10 µm thickness. The THz electric field transmitted through the antenna gap is recorded by electrooptic sampling. By focusing the 800 nm, sub-20 fs sampling pulses, we achieve a spatial resolution of some 3 µm, which is 1/3 to 1/8 of the antenna-gap width. The THz field in the gap displays an enhancement by a factor of up to 4.5 with a pronounced spectral variation, depending sensitively on the antenna-arm length and the gap width. By scanning the 800 nm probe spot laterally through the antenna gap, the spatial variation of the enhancement is determined, reaching the highest values at the edges of the gap. The results are in agreement with simulations of the electric-field distributions by finite-element calculations.

Verbal fluency in essential tremor patients: the effects of deep brain stimulation.

OBJECTIVE: To assess the effects of different frequencies of thalamic Deep-Brain-Stimulation (DBS) on cognitive performance of patients suffering from Essential Tremor (ET). METHODS: In 17 ET-patients with thalamic-DBS, Tremor-Rating-Scale (TRS), standardized phonemic and semantic verbal fluency (VF), Stroop-Color-Word-Test and Digit-span-test were investigated in three randomized stimulation-settings: i) high-frequency stimulation (HFS), ii) low-frequency stimulation (LFS) and iii) OFF-stimulation (DBS-OFF). Paired-samples t-test for TRS and one-way repeated measures analysis of variance for cognitive performance were calculated. RESULTS: Tremor was reduced during HFS (MeanTRS-HFS = 12.9 ± 9.6) compared to DBS-OFF (MeanTRS-OFF = 44.4 ± 19.8, P < .001) and to LFS (MeanTRS-10 Hz = 50.0 ± 24.2; P < .001). While performance of Stroop-task and digit-span remained unaffected by stimulation-settings (P > .05), phonemic and semantic VF differed significantly between the three conditions (FPvf = 5.28, FSvf = 3.41, both P < .05). Post-hoc comparisons revealed significant differences for both phonemic and semantic VF between LFS (MeanPvf-10 Hz = 54.6 ± 9.2, MeanSvf-10 Hz = 56.4 ± 7.9) and HFS (MeanPvf-ON = 48.3 ± 11.4, MeanSvf-ON = 51.1 ± 11.0, both P < .05), while DBS-OFF (MeanPvf-OFF = 51.2 ± 9.3, MeanSvf-OFF = 53.6 ± 12.9) and HFS and DBS-OFF and LFS did not differ significantly (P > .05). CONCLUSIONS: HFS compared to LFS or DBS-OFF significantly reduced tremor but simultaneously worsened VF while working memory and cognitive inhibition remained unaffected. In contrast, LFS enhanced VF but did not ameliorate tremor. The data emphasize the relevance of thalamocortical loops for verbal fluency but also suggest that more sophisticated DBS-regimes in ET may improve both motor and cognitive performance.

Individualized current-shaping reduces DBS-induced dysarthria in patients with essential tremor.

OBJECTIVE: To investigate in patients with essential tremor (ET) treated with thalamic/subthalamic deep brain stimulation (DBS) whether stimulation-induced dysarthria (SID) can be diminished by individualized current-shaping with interleaving stimulation (cs-ILS) while maintaining tremor suppression (TS). METHODS: Of 26 patients screened, 10 reported SID and were invited for testing. TS was assessed by the Tremor Rating Scale and kinematic analysis of postural and action tremor. SID was assessed by phonetic and logopedic means. Additionally, patients rated their dysarthria on a visual analog scale. RESULTS: In 6 of the 10 patients with ET, DBS-ON (relative to DBS-OFF) led to SID while tremor was successfully reduced. When comparing individualized cs-ILS with a non-current-shaped interleaving stimulation (ILS) in these patients, there was no difference in TS while 4 of the 6 patients showed subjective improvement of speech during cs-ILS. Phonetic analysis (ILS vs cs-ILS) revealed that during cs-ILS there was a reduction of voicing during the production of voiceless stop consonants and also a trend toward an improvement in oral diadochokinetic rate, reflecting less dysarthria. Logopedic rating showed a trend toward deterioration in the diadochokinesis task when comparing ON with OFF but no difference between ILS and cs-ILS. CONCLUSION: This is a proof-of-principle evaluation of current-shaping in patients with ET treated with thalamic/subthalamic DBS and experiencing SID. Data suggest a benefit on SID from individual shaping of current spread while TS is preserved. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that in patients with ET treated with DBS with SID, individualized cs-ILS reduces dysarthria while maintaining tremor control.

Tractography-guided stimulation of somatosensory fibers for thalamic pain relief.

BACKGROUND: The spinothalamocortical tract (STC) is seen as a neural tract responsible for or involved in the generation or transmission of thalamic pain. Either the thalamus itself or the posterior limb of the internal capsule (PLIC) are targets for deep brain stimulation (DBS) in patients with thalamic pain, but due to its low contrast, conventional MRI cannot visualize the STC directly. OBJECTIVES: To show the feasibility of integrating diffusion tensor imaging-based tractography into the stereotactic treatment planning for identification of an object-oriented lead trajectory that allows STC-DBS with multiple electrode contacts. METHODS: Diffusion tensor imaging was performed in 4 patients with thalamic pain. The STC was modeled and integrated into the stereotactic treatment planning for DBS. DBS-lead implantation was done according to trajectory planning along the modeled STC at the level of the PLIC. RESULTS: After implantation, electrode stimulation was possible over a length of more than 20 mm with a tractography-based trajectory along the PLIC part of the STC. After a follow-up of 12 months, pain relief of more than 40% was achieved in 3 of 4 patients with rating on a visual analogue scale. In 1 patient, stimulation failed to reach any long-lasting positive effects. CONCLUSIONS: Integrating tractography data into stereotactic planning of DBS in thalamic pain is technically feasible. It can be used to identify a lead trajectory that allows for multiple contact stimulation along the STC at the level of the PLIC. Due to long-lasting positive stimulation effect, tractography-guided stimulation of sensory fibers seems to be beneficial for thalamic pain relief.

Intracerebral administration of heat-inactivated Staphylococcus epidermidis enhances oncolysis and prolongs survival in a 9L orthotopic gliosarcoma model.

BACKGROUND/AIMS: The association between postoperative infection and prolonged survival in high-grade glioma is still a matter of debate. Previously we demonstrated that the intracerebral (i.c.) injection of heat-inactivated staphylococcal epitopes (HISE) resulted in a well-defined infux of immunocompetent cells across the blood-brain barrier. The present study investigated the potential antitumoral effect of HISE-immunostimulation in an experimental glioma model. METHODS: Wistar rats were intracerebrally implanted with 9L gliosarcoma cells (n=6), 9L cells mixed with HISE (n=12), or phosphate buffered saline (n=4). Tumor growth was measured by serial magnetic resonance imaging (MRI). After death due to the tumor burden, the brains were histopathologically assessed for inflammation and oncolysis. A toxicity assay was performed to quantify potential impairment of HISE on tumor cell growth in vitro. RESULTS: Animals treated by HISE showed a significant increase in average survival and even complete regression of an already established mass in one case. Naïve 9L gliosarcomas failed to recruit significant numbers of systemic immune cells. In contrast, concomitant intracerebral HISE inoculation lead to a oncolysis and a distinct peri- and intratumoral infiltration of macrophages, CD8 and CD4 co-expressing T-lymphocytes in two thirds of the tumor-bearing animals. The toxicity screening showed HISE-mediated oncolysis to be ineffective ex vivo. CONCLUSION: This study describes a novel approach for combatting malignant glioma using inactivated staphylococci as potent immunomodulators. Our results provide an outline for investigating the strategic potential of bacteria as emerging future therapeutics.

Intracranial ependymoma: long-term results in a series of 21 patients treated with stereotactic (125)iodine brachytherapy.

BACKGROUND: We evaluated the long-term outcome in patients harboring intracranial ependymomas treated with interstitial brachytherapy (IBT). METHODS: Twenty-one patients (M/F = 9/12; median age: 29 years; range: 8-70 years), diagnosed with intracranial ependymoma (1 WHO I, 11 WHO II, 9 WHO III) were treated with IBT using stereotactically implanted (125)Iodine seeds between 1987 and 2010, either primarily, as adjuvant therapy following incomplete resection, or as salvage treatment upon tumor recurrence. Sixteen of 21 patients underwent microsurgical resection prior to IBT; in 5 patients, IBT was performed primarily after stereotactic biopsy for histological diagnosis. The cumulative tumor surface dose ranged from 50-65 Gy treating a median tumor volume of 3.6 ml (range, 0.3-11.6 ml). A median follow-up period of 105.3 months (range, 12.7-286.2 months) was evaluated. RESULTS: Actuarial 2-, 5- and 10-years overall- and disease-specific survival rates after IBT were each 90% and 100% at all times for ependymomas WHO I/II, for anaplastic ependymomas WHO III 100%, 100%, 70% and 100%, 100%, 86%, respectively. The neurological status of seven patients improved, while there was no change in 12 and deterioration in 2 patients, respectively. Follow-up MR images disclosed a complete tumor remission in 3, a partial remission in 12 and a stable disease in 6 patients. Treatment-associated morbidity only occurred in a single patient. CONCLUSIONS: This study shows that stereotactic IBT for intracranial ependymomas is safe and can provide a high degree of local tumor control. Due to the low rate of side effects, IBT may evolve into an attractive alternative to microsurgery in ependymomas located in eloquent areas or as a salvage treatment.

Deep brain stimulation of the ventral intermediate nucleus in patients with essential tremor: stimulation below intercommissural line is more efficient but equally effective as stimulation above.

BACKGROUND: The posterior subthalamic area (PSA), ventral to the intercommissural line (ICL) and the ventral intermediate nucleus (VIM), has been suggested as a promising target for deep brain stimulation (DBS) in patients suffering from essential tremor (ET). In this study the clinical benefit of VIM and PSA DBS on postural tremor suppression was systematically evaluated in a two step approach with a 3D ultrasound kinematic analysis tool. METHODS: We defined the exact position of 40 VIM-DBS-electrodes from 21 ET patients. In a first experiment with a subgroup of electrodes we subsequently activated a thalamic and a contact below ICL (sub-ICL) with equal parameter settings for within subject comparison. In a second step, we divided all electrodes into two groups, i.e. one group with activated thalamic and the other group with activated contacts below ICL and performed a group comparison under patients' individual stimulation parameters. Here, the corrected amplitude required for tremor suppression was analyzed separately for both groups. RESULTS: Within subject comparison with equal parameter settings revealed a significant improvement of sub-ICL compared to thalamic stimulation. In contrast, group comparison under patients' individual stimulation did not show any significant difference in tremor suppression between VIM and PSA DBS. Although higher corrected stimulation amplitude was needed in the thalamic group this difference was not significant. CONCLUSION: The data suggest that sub-ICL stimulation may be more efficient compared to thalamic stimulation but equally effective when patients' individual stimulation parameters are used.

Stereotactic 125iodine brachytherapy for the treatment of singular brain metastases: closing a gap?

BACKGROUND: Brain metastases represent the most common intracranial tumors and are associated with very poor prognosis. OBJECTIVE: To investigate the feasibility, survival, and cerebral disease control of patients with singular brain metastases treated with stereotactic 125iodine brachytherapy (SBT), to identify prognostic factors, and to compare results with other local treatment methods. METHODS: Complications, survival (overall and separated by recursive partitioning analysis [RPA] classes), and local and distant disease control were evaluated retrospectively in 90 patients. Prognostic factors were identified by forming subgroups of patients based on age, Karnofsky Performance Status, status of extracranial disease, interval since initial diagnosis, absence/presence of prior whole-brain radiation therapy, localization, morphology, and tumor volume. RESULTS: There was no treatment-related mortality, and morbidity was transient and low (3.3%). Median survival was 8.5 months overall and 18.1 months for RPA class 1 patients. After 1 year, the actuarial incidence of local and distant cerebral relapse was 5.4% and 46.4%, respectively. Karnofsky Performance Status ≥ 70 (P < .002), stable systemic disease (P < .02), RPA class 1 (P < .02), and a prolonged (> 12 month) interval between initial diagnosis and SBT (P < .05) significantly improved survival. No significant influence of previous whole-brain radiation therapy on survival or cerebral disease relapse was found. CONCLUSION: SBT represents a safe, minimally invasive, and, compared with SRS and microsurgery, a similarly effective local treatment option in terms of survival and cerebral disease control. It allows histological (re-)evaluation and treatment within 1 stereotactic operation. Because it is less restricted by tumor localization or size, it greatly advances local treatment options, and on the basis of its favorable biological irradiation effect, SBT does not limit additional irradiation treatment in the event of disease relapse.

Deep brain stimulation in the nucleus ventralis intermedius in patients with essential tremor: habituation of tremor suppression.

In patients with essential tremor (ET) already treated with chronic deep brain stimulation (DBS) of the nucleus ventralis intermedius (VIM) we investigated whether optimization of stimulation parameters could improve clinical tremor suppression, and whether this putative effect could be sustained over time. Twenty-three ET patients with VIM-DBS participated in the prospective study. All electrode contacts were tested systematically and stimulation parameters were optimized over the course of 2 days. Clinical tremor rating scale (TRS) was videotaped before, directly after the optimization and at a 10 weeks follow-up and evaluated blindly and independently by two clinicians. For stimulation effect optimization we increased the number of active contacts whereas the total charge applied to the tissue was kept constant. TRS hemi-body scores decreased significantly after optimization. At the 10 weeks follow-up, however, the improvement had faded and was no longer significant. The activities of daily living (ADL) remained significantly improved. Systematic optimization of VIM-DBS parameters in ET patients leads to a short term improvement which habituates over time. Our results provide further evidence for a tolerance effect in chronic VIM stimulation thereby suggesting that frequently alternating stimulation protocols should be tested in future studies of ET patients treated with VIM-DBS.

Multimodal localization of electrodes in deep brain stimulation: comparison of stereotactic CT and MRI with teleradiography.

OBJECTIVE: In cross-sectional imaging, like CT or MRI, electrodes for deep brain stimulation are visualized by an artifact, which can differ from the real physical size of the electrode and even have an asymmetric appearance on MRI. The accuracy of such artifact-based estimation of the real position of the electrode using CT or MRI is investigated here. Stereotactic teleradiography was used as the gold standard. METHODS: Twenty-three patients with implanted electrodes in the subthalamic nucleus (DBS type 3389; Medtronic, Minneapolis, Minn., USA) were included in a retrospective study on multimodal estimation of electrode position by 2 raters. Short spoiled gradient echo MRI (n = 10) and multi-row CT (n = 13) data were compared with teleradiography. RESULTS: Mean radial differences between CT and X-ray for both raters were 0.6 +/- 0.2 and 0.7 +/- 0.3 mm, with maximum values of 1.0 and 1.2 mm, respectively. Both raters showed quite similar assessments in their ratings. Mean radial differences between MRI and X-ray were 1.2 +/- 0.4 and 1.1 +/- 0.4 mm, with maximum values of 1.7 and 2.2 mm. Concordance of the assessment was lower compared to CT. CONCLUSION: Spoiled gradient echo MR imaging cannot be recommended for visual localization of the quadripolar macroelectrode type 3389 from Medtronic. In contrast, CT imaging in absolute terms and with quite similar assessments by both raters is intra- and postoperatively a satisfactory alternative to teleradiography.

Linear accelerator radiosurgery for pituitary macroadenomas: a 7-year follow-up study.

BACKGROUND: A prospective study was conducted to assess the efficacy and side effects of linear accelerator (LINAC)-based radiosurgery (RS) performed with a reduced dose of therapeutic radiation for patients with surgically inaccessible pituitary macroadenomas. METHODS: From August 1990 through January 2004, 175 patients with pituitary macroadenomas were treated with LINAC-RS according to a prospective protocol. To minimize the risk for radiation-induced damage of the pituitary function, the therapeutic dose to be applied was limited to 20 grays. RESULTS: Among 175 patients, 142 patients who had a minimum follow-up of 12 months (mean +/- standard deviation, 81.9 +/- 37.2 months) were included in the current study. The local tumor control rate was 96.5%, and the tumor response rate was 32.4%. The mean time (+/- standard deviation) from LINAC-RS to normalization of pathologic hormone secretion was 36.2 +/- 24.0 months. The probability for normalization was 34.3% at 3 years and 51.1% at 5 years. The frequency of endocrine cure (defined as the normalization of hormone secretion without specific medication intake) was 35.2% (mean +/- standard deviation time to cure, 42.1 +/- 25.0 months). Patients with Cushing disease had a statistically significant greater chance of achieving a cure (P = .001). Side effects of LINAC-RS were deterioration of anterior pituitary function (12.3%), radiation-induced tissue damage (2.8%), and radiation-induced neuropathy (1.4%). CONCLUSIONS: LINAC-RS using a lower therapeutic radiation dose achieved local tumor control and normalization or cure of hormone secretion comparable to the results achieved with gamma-knife RS. Compared with the latter, the time to normalization or endocrine cure was delayed, most probably as a result of dose reduction. However, the lower therapeutic radiation dose did not prevent radiation-induced damage of pituitary function completely.