Concomitant lorazepam use and antidepressive efficacy of repetitive transcranial magnetic stimulation in a naturalistic setting.

BACKGROUND/OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) has been established as an effective therapeutic intervention for the treatment of depression. Preliminary data suggest that the efficacy of rTMS is reduced in patients taking benzodiazepines (BZD). Here, we use real-world data from a large sample to investigate the influence of lorazepam on the effectiveness of rTMS. METHODS: From a retrospective cohort of clinically depressed patients that were treated with rTMS, we compared 176 patients not taking any BZD with 73 patients taking lorazepam with respect to changes in the Hamilton Depression Rating Scale (HRDS). RESULTS: Both groups improved during rTMS according to HRDS scores, but the amelioration of symptoms was significantly less pronounced in patients taking lorazepam (18% vs. 38% responders in the non-lorazepam group). We could not see any association of intake regimen of lorazepam with response in rTMS. CONCLUSION: Our observational study suggests that intake of lorazepam impedes the response to rTMS. The impact of lorazepam and other BZD on rTMS should receive more attention and be further investigated in prospective, hypothesis-based treatment studies to determine causal relationships between medication treatments and outcome. This could lead to specific recommendations for pharmacological treatment for depressed patients undergoing rTMS.

Antidepressant effect of repetitive transcranial magnetic stimulation is not impaired by intake of lithium or antiepileptic drugs.

INTRODUCTION: The effect of concomitant medication on repetitive transcranial magnetic stimulation (rTMS) outcomes in depression remains understudied. Recent analyses show attenuation of rTMS effects by antipsychotic medication and benzodiazepines, but data on the effects of antiepileptic drugs and lithium used as mood stabilizers or augmenting agents are sparse despite clinical relevance. Preclinical electrophysiological studies suggest relevant impact of the medication on treatment, but this might not translate into clinical practice. We aimed to investigate the role of lithium (Li), lamotrigine (LTG) and valproic acid (VPA) by analyzing rTMS treatment outcomes in depressed patients. METHODS: 299 patients with uni- and bipolar depression treated with rTMS were selected for analysis in respect to intake of lithium, lamotrigine and valproic acid. The majority (n = 251) were treated with high-frequency (10-20 Hz) rTMS of the lDLPFC for an average of 17 treatment sessions with a figure-of-8 coil with a MagVenture system aiming for 110% resting motor threshold, and smaller groups of patients were being treated with other protocols including intermittent theta-burst stimulation and bilateral prefrontal and medial prefrontal protocols. For group comparisons, we used analysis of variance with the between-subjects factor group or Chi-Square Test of Independence depending on the scales of measurement. For post-hoc tests, we used least significant difference (LSD). For differences in treatment effects between groups, we used an ANOVA with the between-subjects factor group (groups: no mood stabilizer, Li, LTG, VPA, Li + LTG) the within-subjects factor treatment (pre vs. post treatment with rTMS) and also Chi-Square Tests of independence for response and remission. RESULTS: Overall, patients showed an amelioration of symptoms with no significant differences for the main effect of group and for the interaction effect treatment by group. Based on direct comparisons between the single groups taking mood stabilizers against the group taking no mood stabilizers, we see a superior effect of lamotrigine, valproic acid and combination of lithium and lamotrigine for the response and remission rates. Motor threshold was significantly and markedly higher for patients taking valproic acid. CONCLUSION: Being treated with lithium, lamotrigine and valproic acid had no relevant influence on rTMS treatment outcome. The results suggest there is no reason for clinicians to withhold or withdraw these types of medication from patients who are about to undergo a course of rTMS. Prospective controlled work on the subject is encouraged.

Multimodal imaging of a tescalcin (TESC)-regulating polymorphism (rs7294919)-specific effects on hippocampal gray matter structure.

In two large genome-wide association studies, an intergenic single-nucleotide polymorphism (SNP; rs7294919) involved in TESC gene regulation has been associated with hippocampus volume. Further characterization of neurobiological effects of the TESC gene is warranted using multimodal brain-wide structural and functional imaging. Voxel-based morphometry (VBM8) was used in two large, well-characterized samples of healthy individuals of West-European ancestry (Münster sample, N=503; SHIP-TREND, N=721) to analyze associations between rs7294919 and local gray matter volume. In subsamples, white matter fiber structure was investigated using diffusion tensor imaging (DTI) and limbic responsiveness was measured by means of functional magnetic resonance imaging (fMRI) during facial emotion processing (N=220 and N=264, respectively). Furthermore, gene x environment (G × E) interaction and gene x gene interaction with SNPs from genes previously found to be associated with hippocampal size (FKBP5, Reelin, IL-6, TNF-α, BDNF and 5-HTTLPR/rs25531) were explored. We demonstrated highly significant effects of rs7294919 on hippocampal gray matter volumes in both samples. In whole-brain analyses, no other brain areas except the hippocampal formation and adjacent temporal structures were associated with rs7294919. There were no genotype effects on DTI and fMRI results, including functional connectivity measures. No G × E interaction with childhood maltreatment was found in both samples. However, an interaction between rs7294919 and rs2299403 in the Reelin gene was found that withstood correction for multiple comparisons. We conclude that rs7294919 exerts highly robust and regionally specific effects on hippocampal gray matter structures, but not on other neuropsychiatrically relevant imaging markers. The biological interaction between TESC and RELN pointing to a neurodevelopmental origin of the observed findings warrants further mechanistic investigations.

The influence of field strength on the apparent diffusion coefficient of 3He gas in human lungs.

The (3)He MR diffusion signal is sensitive to lung microstructure, but it is also affected by the presence of background field inhomogeneities induced by the magnetic susceptibility difference at the air-tissue interface. These susceptibility-induced gradients, which are dependent on field strength, have been assumed negligible in theoretical models used to extract airway morphometric information from (3)He MR diffusion data at field strengths up to 4.7 T. In this work, the effect of susceptibility gradients on (3)He apparent diffusion coefficient is demonstrated with experiments in healthy volunteers at two B(0) field strengths: 1.5 and 3 T. Apparent diffusion coefficient values obtained at 3 T were systematically larger than at 1.5 T, demonstrating that susceptibility effects are statistically significant even at clinical field strengths (B(0) ≤ 3 T) and introduce biases in the estimates of airway dimensions (e.g., mean linear intercept up to 17% larger at 3 T than 1.5 T). Susceptibility effects should be taken into account in the development of theoretical models of lung (3)He MR diffusion and considered when interpreting (3)He apparent diffusion coefficients obtained at different B(0).

Acquisition of ³He ventilation images, ADC, T2* and B1 maps in a single scan with compressed sensing.

In imaging of human lungs with hyperpolarised noble gases, measurements of apparent diffusion coefficient (ADC) and relaxation time provide valuable information for the assessment of lung microstructure. In this work, a sequence was developed for interleaved acquisition of ventilation images, ADC, T(2)* and flip angle maps in a single scan from the human lungs with a single dose of inhaled (3)He at 3 T. Spatially registered ventilation images with parametric maps were obtained. The total acquisition time was reduced by random undersampling of the k-space and reconstruction using compressed sensing (CS). The gain in speed was used for an increase in spatial resolution. Mean ADC values from the fully sampled and undersampled CS data exhibit no statistically significant difference in a given subject. The mean T(2)* values, however, were found to differ significantly, which is attributed to the combined effect of low signal-to-noise ratio (SNR) of the fully sampled data and the smoothing effect inherent in CS reconstruction.

Participation of the sperm proteasome during in vitro fertilisation and the acrosome reaction in cattle.

In this work, we have investigated the role of the bovine sperm proteasome during in vitro fertilisation (IVF) and the acrosome reaction (AR). Motile spermatozoa, obtained by a swim-up method in Sperm-Talp medium, were capacitated for 3.5 h and incubated in the presence or absence of the specific proteasome inhibitor epoxomicin for 30 and 60 min. Then, the spermatozoa were co-incubated with mature bovine cumulus oocytes and after 48 h the cleavage rate of inseminated oocytes was evaluated. In addition, we evaluated the participation of the sperm proteasome during the progesterone-induced AR. Capacitated spermatozoa were incubated for 30 min with or without epoxomicin, then progesterone was added and the ARs were evaluated using the dual fluorescent staining technique 'Hoechst and chlortetracycline'. The results indicate that the proteasome inhibitor decreased the cleavage rate of oocytes inseminated with treated spermatozoa. In addition, acrosomal exocytosis levels were statistically significantly higher in the samples treated with the AR inducer progesterone than in control samples in the absence of the inducer. However, the progesterone-induced AR was significantly reduced by previous treatment of the spermatozoa with epoxomicin (P < 0.001). These observations indicate that the bovine sperm proteasome participates in the IVF and AR processes.

[Susac syndrome: an interdisciplinary challenge]. / Susac-Syndrom : Eine interdisziplinäre Herausforderung.

Susac syndrome, named after John Susac, the first to describe this condition, is characterized by the clinical triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. Although certainly a rare disease, Susac syndrome needs to be considered in the differential diagnosis of a broad variety of diseases. The pathogenesis is not yet clear. Autoimmune processes leading to damage and inflammation-related occlusion of the microvessels in brain, retina, and inner ear are thought to play a causal role. The diagnosis is based primarily on the clinical presentation, the documentation of branch retinal artery occlusion by fluorescence angiography, and characteristic findings on cerebral MRI. Usually, immunosuppressive therapy is required, though controlled therapy trials are missing so far. The intention of this review article is to raise awareness of this disease among neurologists, psychiatrists, ophthalmologists, and ENT specialists as a high number of unreported cases probably exists. Accordingly, the focus is on the clinical presentation and the diagnostic approach.

Trypsin and chymotrypsin are involved in the progesterone-induced acrosome reaction in canine spermatozoa.

Acrosomal proteases allow the spermatozoon not only to cross the cumulus cells and penetrate the zona pellucida of the oocyte, but also they are needed for the acrosome reaction process (AR). The present study evaluated in vitro the role of trypsin and chymotrypsin in the acrosome reaction of canine spermatozoa by means of protease inhibitors. Spermatozoa obtained from the second fraction of the ejaculate and devoid of seminal plasma were re-suspended in canine capacitation medium (CCM) and incubated at 38.5 degrees C in 5% CO(2). After 2 h (period of sperm capacitation), aliquots of sperm suspension were incubated separately with trypsin inhibitor NPGB (p-nitrophenyl-p'-guanidino-benzoate); TI (Trypsin inhibitor I-S Type from soybean) and with chymotrypsin inhibitor TPCK (N-tosyl-L-phenylalanine-chloromethyl-ketone) for 30 min. The AR was induced with progesterone and evaluated using the dual fluorescent staining technique 'Hoechst and chlortetracycline'. Acrosomal exocytosis levels were statistically significant higher in the samples treated with progesterone than in the control without inducer. However, the trypsin inhibitors NPGB, TI and the chymotrypsin inhibitor TPCK reduced the percentage of AR when compared with the control with progesterone and without inhibitor (p < 0.001), where the AR values were 45.63 +/- 3.8%, 51.63 +/- 2.8%, 58.38 +/-4.1% and 71.25 +/- 4.9%, respectively. These results show that trypsin and chymotrypsin inhibitors are effective in blocking the acrosome reaction induced by progesterone in canine; in addition, they suggest the participation of respective proteases in the AR process in this species.

Dynamics of electron-phonon scattering: crystal- and angular-momentum transfer probed by resonant inelastic x-ray scattering.

Experimentally, we observe angular-momentum transfer in electron-phonon scattering, although it is commonly agreed that phonons transfer mostly linear momentum. Therefore, the incorporation of angular momentum to describe phonons is necessary already for simple semiconductors and bears significant implications for the formation of new quasiparticles in correlated functional materials. Separation of linear and angular-momentum transfer in electron-phonon scattering is achieved by highly selective excitations on the femtosecond time scale of resonant inelastic x-ray scattering.

Pattern and progression of white-matter changes in a case of posterior cortical atrophy using diffusion tensor imaging.

BACKGROUND: The progression of white-matter changes in a case of posterior cortical atrophy (PCA) was examined over a period of 15 months using diffusion tensor imaging (DTI) and the association with neuropsychological variables was studied. PATIENT AND METHODS: A PCA patient was observed over a period of 15 months. DTI and volumetric magnetic resonance imaging were obtained at visit 1 and 15 months later. Fractional anisotropy (FA) and volumetric changes were compared with findings in a typical case of Alzheimer disease (AD) and in 65 healthy volunteers, and the association of neuropsychological deficits with these changes was studied. RESULTS: Reduction in FA was focused on the occipital lobe in the early stages of PCA. During the 15-month period, the FA values of the PCA patient tended to align with the FA ratios of the AD patient, with a more pronounced FA reduction in the parietal lobes, as opposed to a stable FA level in the occipital lobe. In addition to the DTI changes, clinical and neuropsychological symptoms deteriorated further. Brain volumes (grey matter, white matter and total normalised brain volume) of the PCA patient were substantially decreased compared with the control group, but loss of tissue volumes showed only marginal progression between visit 1 and 2. CONCLUSIONS: The findings suggest that PCA starts as distinct clinical syndrome but in its later course might turn into a final pathway shared with AD. DTI might be helpful in detecting changes in cerebral white matter during disease progression in PCA patients.

New non-magnetically ordered heavy-fermion system CeTiGe.

Investigations of the susceptibility, electrical resistivity, specific heat and thermopower of CeTiGe at low temperatures show that this compound is a Kondo lattice system with an enhanced Sommerfeld coefficient γ≈0.3 J K(-2) mol(-1) and where the whole J = 5/2 multiplet is involved in the formation of the ground state. No magnetic order was observed down to 0.4 K. In the temperature range below 10 K we observed Fermi-liquid behavior as indicated by a ρ(T)∼T(2) dependence in the electrical resistivity and a linear specific heat and thermopower. Because of these results we classify CeTiGe as a moderate heavy-fermion system with a non-magnetic ground state.

[Extreme obesity-particular aspect of invasive and noninvasive ventilation]. / Adipositas (permagna) ­ Besonderheiten bei der invasiven und nichtinvasiven Beatmung.

The obesity rate is increasing worldwide and the percentage of obese patients in the intensive care unit (ICU) is rising concomitantly. Ventilatory support strategies in obese patients must take into account the altered pathophysiological conditions. Unfortunately, prospective randomized multicenter trials on this subject are lacking. Therefore, current strategies are based on the individual experiences of ICU physicians and single-center studies. Noninvasive ventilation (NIV) in critically ill patients with acute respiratory failure and obesity hypoventilation syndrome (OHS) is an efficient treatment option and should be provided as early as possible is an effort to avoid intubation. Patient positioning is also crucial: half-sitting positions (>45°) improve lung compliance and functional residual capacity in patients with respiratory failure. Transpulmonary pressure measurements or the Acute Respiratory Distress Syndrome (ARDS) Network tables may help to adjust the optimal positive end-expiratory pressure (PEEP). The tidal volume should be adapted to the ideal and not the actual bodyweight (Vt = 6 ml/kg of ideal bodyweight) to avoid lung damage and (additional) right ventricular stress. Under particular conditions, inspiratory pressures >30 cmH2O may be tolerated for a limited duration. Early tracheostomy combined with termination/reduction of sedation and relaxation is controversy discussed in the literature as a therapeutic option during invasive ventilation of morbidly obese patients. However, data on early tracheotomy in obese respiratory failure patients are rare and this should be regarded as an individual treatment attempt only. In cases of refractory lung failure, venovenous extracorporeal membrane oxygenation (vv-ECMO) is an option despite anatomic changes in morbid obesity.

Effect of protease inhibitors on the acrosome reaction and sperm-zona pellucida binding in bovine sperm.

Acrosomal proteases participate in several events during fertilization process and are necessary during the acrosome reaction (AR) and sperm-zona pellucida (ZP) binding process. In this study, the participation of sperm trypsin-like, chymotrypsin-like, and metalloprotease enzymes in the AR and ZP binding in cattle was investigated using protease inhibitors. Motile bovine sperm were obtained by a swim-up method (4 x 10(6) cells / ml) in Brackett and Oliphant medium. The sperm were capacitated and then incubated with Antithrombin III (trypsin and chymotrypsin inhibitor); N-alpha-p-tosyl-l-lysine-chloromethyl-ketone (trypsin inhibitor); Trypsin inhibitor (I-S Type from soybean); N-tosyl-l-phenylalanine-chloromethyl-ketone (chymotrypsin inhibitor); or disodium salt from the hydrated ethylenediaminetetraacetic acid (metalloprotease inhibitor). Then, the AR was induced with lysophosphatidylcholine and evaluated with the double stain technique. Sperm-zona binding capacity was evaluated using cumulus cell-free oocytes. A significant decrease (p < 0.05) in the percent of true acrosome-reacted sperm was observed only in cells incubated with trypsin (10.2 +/- 1%) and chymotrypsin inhibitors (18.5 +/- 1%) in relation to the control (52.2 +/- 1%). Treatment with the metalloprotease inhibitor did not affect the AR percentage (51.8 +/- 1%). On the contrary, there was no significant change in the number of sperm bound to the ZP with any of the inhibitors used. The results suggest a role for trypsin and chymotrypsin proteases, but not metalloproteases, in the AR in bovine sperm. In addition, these proteases do not seem to be involved in the binding of bovine sperm to the ZP.

Evaluation of Quality of Life Outcomes Following Palliative Treatment of Bone Metastases with Magnetic Resonance-guided High Intensity Focused Ultrasound: An International Multicentre Study.

AIMS: To determine quality of life (QoL) outcomes after palliation of pain from bone metastases using magnetic resonance-guided high intensity focused ultrasound (MR-guided HIFU), measured using the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C15-PAL and the QLQ-BM22 questionnaires. MATERIALS AND METHODS: Twenty patients undergoing MR-guided HIFU in an international multicentre trial self-completed the QLQ-C15-PAL and QLQ-BM22 questionnaires before and on days 7, 14, 30, 60 and 90 post-treatment. Descriptive statistics were used to represent changes in symptom and functional scales over time and to determine their clinical significance. QoL changes were compared in pain responders and non-responders (who were classified according to change in worst pain score and analgesic intake, between baseline and day 30). RESULTS: Eighteen patients had analysable QoL data. Clinically significant improvements were seen in the QoL scales of physical functioning, fatigue, appetite loss, nausea and vomiting, constipation and pain in the 53% of patients who were classified as responders at day 30. No significant changes were seen in the 47% of patients who were non-responders at this time point. CONCLUSION: Local treatment of pain from bone metastases with MR-guided HIFU, even in the presence of disseminated malignancy, has a substantial positive effect on physical functioning, and improves other symptomatic QoL measures. This indicated a greater response to treatment over and above pain control alone. MR-guided HIFU is non-invasive and should be considered for patients with localised metastatic bone pain and poor QoL.

Scalp position and efficacy of transcranial magnetic stimulation.

OBJECTIVE: To assess the impact of the scalp site on the biological effects of TMS. METHODS: We performed high-resolution, three-dimensional whole head magnetic resonance imaging (MRI) in a healthy subject, systematically measured the scalp-to-cortex distance across the head and calculated the resulting electric field in the superficial cortex. RESULTS: The variability in scalp-to-cortex distance led to differences in calculated cortical electric field strengths of a factor of two. A major portion of this variability was explained by a lateral to medial gradient with scalp-to-cortex distances being greatest close to the midline and smallest towards the temporal coordinates. CONCLUSIONS: Because of the medio-lateral gradient in scalp-to-cortex distance interventions tailored on the basis of effects of TMS in the motor system will systematically induce stronger than expected electric currents when performed laterally to the motor spot. SIGNIFICANCE: The biological effects of TMS outside the motor spot may be markedly different from those observed in the motor system and this should be taken into account to optimize TMS for the evaluation or treatment of neuropsychiatric disorders.

Evidence for a neural correlate of a framing effect: bias-specific activity in the ventromedial prefrontal cortex during credibility judgments.

BACKGROUND: Neural processes within the medial prefrontal cortex play a crucial role in assessing and integrating emotional and other implicit information during decision-making. Phylogenetically, it was important for the individual to assess the relevance of all kinds of environmental stimuli in order to adapt behavior in a flexible manner. Consequently, we can in principle not exclude that environmental information covertly influences the evaluation of actually decision relevant facts ("framing effect"). OBJECTIVE: To test the hypothesis that the medial prefrontal cortex is involved into a framing effect we employed functional magnetic resonance imaging (fMRI) during a binary credibility judgment task. METHODS: Twenty-one subjects were asked to judge 30 normalized news magazine headlines by forced answers as "true" or "false". To confound the judgments by formally irrelevant framing information we presented each of the headlines in four different news magazines characterized by varying credibility. For each subject the susceptibility to the judgment confounder (framing information) was assessed by magazine-specific modifications of the answers given. RESULTS: We could show that individual activity changes of the ventromedial prefrontal cortex during the judgments correlate with the degree of an individual's susceptibility to the framing information. CONCLUSION: We found (i) a neural correlate of a framing effect as postulated by behavioral decision theorists that (ii) reflects interindividual differences in the degree of the susceptibility to framing information.

Assessment of hemispheric language lateralization: a comparison between fMRI and fTCD.

The cerebral blood flow velocity (CBFV) in the basal arteries during a word-generation task was assessed by functional transcranial Doppler ultrasonography (fTCD) and by functional magnetic resonance imaging (fMRI). The study investigates how event-related CBFV modulations in the middle cerebral artery (MCA) relate to regional cerebral blood flow (rCBF) changes. Both fMRI and fTCD were used in 13 subjects (7 men, 6 women, aged 21 to 44 years). The maximum difference of relative CBFV changes between the left and right MCA during the word-generation task was used as the language laterality index (LIfTCD). For the fMRI examination during the nearly identical language task, the corresponding index was defined by LIfMRI = 100(N(L) - N(R))/(N(L) + N(R)), where N(L) and N(R) refer to the numbers of voxels activated in the left and right hemisphere, respectively. The evoked CBFV changes expressed by LIfTCD and the corresponding laterality index, LIfMRI, estimated by fMRI showed a close linear relation (regression analysis: r = 0.95, p < 0.0001). The results of this study demonstrate that language-related velocity changes in the MCAs relate to rCBF increases in a linear fashion. Since the laterality indices assessed by fMRI and fTCD are in such close agreement both techniques can therefore be used in a complementary way.

Language and spatial attention can lateralize to the same hemisphere in healthy humans.

BACKGROUND: Disorders of language classically occur after left brain lesions, and disorders of spatial attention after right brain lesions. It is unclear whether the hemispheric dissociation of functions is a fixed pattern of brain organization. OBJECTIVE: The authors determined whether lateralization of language and lateralization of spatial attention also dissociate in people with atypical (i.e., right hemispheric) language dominance. METHODS: The authors selected 10 subjects with typical, i.e., left hemispheric, and 10 with atypical, i.e., right hemispheric, language representation on a random basis from a sample of 326 healthy volunteers examined with functional transcranial Doppler sonography (fTCD) for language dominance. In these subjects, hemispheric lateralization of cerebral perfusion during a line bisection task was determined with fTCD. RESULTS: The authors found a dissociation between dominance for language and spatial attention in all but four subjects. In the latter subjects, there was a significant lateralization to the right hemisphere for both tasks. The four subjects showed normal intellectual, linguistic, and spatial performance, with normal EEG and MRI scans of the brain. CONCLUSION: Even in the absence of brain pathology, the same hemisphere can be dominant in control of both language and spatial attention.

Cerebral hemodynamics during electrically induced seizures.

Electroconvulsive therapy (ECT) is an appropriate clinical model to investigate blood flow during seizures. In this study cerebral blood flow velocity (CBFV) was measured during 40 ECTs in 10 patients by means of transcranial Doppler sonography. EEG was recorded continuously. Under general anesthesia, the pre-convulsive blood flow velocity (Vmean) decreased significantly. After ECT, we measured a dramatic increase in Vmean which was significantly greater in the left MCA than in the right MCA. After termination of seizures, flow velocities returned to baseline levels. The striking increase in cerebral blood flow velocity reflects excessive cerebral metabolism during convulsive neuronal activation. The left hemisphere seems to be more sensitive to electrical stimuli as was indicated by its predominant augmentation of CBFVs.

Successive activation of both cerebral hemispheres during cued word generation.

Most humans have a left hemispheric dominance for language. However, during diagnostic language testing there also is activation of the right hemisphere, which is probably related to attention. To investigate further the role of attention during language production we monitored cerebral blood flow velocities in the middle cerebral arteries by continuous bilateral transcranial Doppler ultrasonography (TCD) in nine right-handed subjects. During cued word generation, a successive activation of the right hemisphere in the preparatory phase, and of the left hemisphere during word searching was demonstrated. These findings indicate that attentional processes precede verbal activation and that the two procedures can be separated by comparative blood flow velocity measurement.