The cerebellar (para)flocculus:A review on its auditory function and a possible role in tinnitus

The cerebellum is historically considered to be involved in motor control and motor learning. However, it is also a site of multimodal sensory and sensory-motor integration, implicated in auditory processing. The flocculus and paraflocculus are small lobes of the cerebellum, in humans located in the cerebellopontine angle. The last two decades, both structures have been a subject of interest in hearing loss and tinnitus research. The current review summarizes insights on the auditory function of the (para)flocculus and its contribution to hearing loss and tinnitus. This leads to the hypothesis of a feedback loop between the paraflocculus and the auditory cortex. Disruption of this loop may be instrumental in both maintaining tinnitus and reducing tinnitus. Although the research mostly has been performed in animals, the implications in humans are also discussed. If the (para)flocculus indeed comprises an auditory function and is part of a tinnitus-mechanism, this would potentially open up new treatment options that involve direct intervention at the (para)flocculus

Intervention for unruptured high-grade intracranial dural arteriovenous fistulas:a multicenter study

OBJECTIVE The risk-to-benefit profile of treating an unruptured high-grade dural arteriovenous fistula (dAVF) is not clearly defined. The aim of this multicenter retrospective cohort study was to compare the outcomes of different interventions with observation for unruptured high-grade dAVFs.METHODS The authors retrospectively reviewed dAVF patients from 12 institutions participating in the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR). Patients with unruptured high-grade (Borden type II or III) dAVFs were included and categorized into four groups (observation, embolization, surgery, and stereotactic radiosurgery [SRS]) based on the initial management. The primary outcome was defined as the modified Rankin Scale (mRS) score at final follow-up. Secondary outcomes were good outcome (mRS scores 0-2) at final follow-up, symptomatic improvement, all-cause mortality, and dAVF obliteration. The outcomes of each intervention group were compared against those of the observation group as a reference, with adjustment for differences in baseline characteristics.RESULTS The study included 415 dAVF patients, accounting for 29, 324, 43, and 19 in the observation, embolization, surgery, and SRS groups, respectively. The mean radiological and clinical follow-up durations were 21 and 25 months, respectively. Functional outcomes were similar for embolization, surgery, and SRS compared with observation. With observation as a reference, obliteration rates were higher after embolization (adjusted OR [aOR] 7.147, p = 0.010) and surgery (aOR 33.803, p &lt; 0.001) and all-cause mortality was lower after embolization (imputed, aOR 0.171, p = 0.040). Hemorrhage rates per 1000 patient-years were 101 for observation versus 9, 22, and 0 for embolization (p = 0.022), surgery (p = 0.245), and SRS (p = 0.077), respectively. Nonhemorrhagic neurological deficit rates were similar between each intervention group versus observation.CONCLUSIONS Embolization and surgery for unruptured high-grade dAVFs afforded a greater likelihood of obliteration than did observation. Embolization also reduced the risk of death and dAVF-associated hemorrhage compared with conservative management over a modest follow-up period. These findings support embolization as the first-line treatment of choice for appropriately selected unruptured Borden type II and III dAVFs.</p

The Role of Inflammation in Tinnitus:A Systematic Review and Meta-Analysis

Subjective tinnitus is the perception of sound without the presence of an external source. Increasing evidence suggests that tinnitus is associated with inflammation. In this systematic review, the role of inflammation in subjective tinnitus was studied. Nine animal and twenty human studies reporting inflammatory markers in both humans and animals with tinnitus were included. It was established that TNF-α and IL-1β are increased in tinnitus, and that microglia and astrocytes are activated as well. Moreover, platelet activation may also play a role in tinnitus. In addition, we elaborate on mechanisms of inflammation in tinnitus, and discuss potential treatment options targeting inflammatory pathways

Electrical modulation of the sympathetic nervous system in order to augment cerebral blood flow: a protocol for an experimental study

Introduction: Cerebral blood flow (CBF) is regulated by several mechanisms. Neurogenic control has been a matter of debate, even though several publications reported the effects of changes in sympathetic tone on CBF. Transcutaneous electrical nerve stimulation and spinal-cord stimulation have been shown to influence peripheral and cerebral blood flow through a sympathetic pathway. The authors hypothesise that certain pathological conditions result in a relative increase in the neurogenic regulation of CBF and that this regulation can be modulated electrically. Methods and analysis: Patients with cerebral vasospasm after subarachnoid haemorrhage will be included. The experimental set-up measures several parameters that are involved in cerebral blood flow regulation in patients with cerebral vasospasm after subarachnoid haemorrhage. Measurements are taken at baseline and with stimulation in several frequencies. An ad hoc statistical analysis is used to evaluate different settings of the electrical stimulation. Autoregulation is evaluated with transfer function analysis and autoregulatory index calculations. Ethics and dissemination: Ethical registration was granted by Medical Review Ethics Committee Groningen (ID METc 2010.123). All participants provide written informed consent on participation. Upon finishing a pilot study to investigate feasibility and effect, either future prospective (randomised) studies will be designed, or other modalities of electrical stimulation will be explored using the same set-up

Cerebellar Gray Matter Volume in Tinnitus

Tinnitus is the perception of sound without an external source. The flocculus (FL) and paraflocculus (PFL), which are small lobules of the cerebellum, have recently been implicated in its pathophysiology. In a previous study, the volume of the (P)FL-complex correlated with tinnitus severity in patients that had undergone cerebellopontine angle (CPA) tumor removal. In this study, the relation between tinnitus and gray matter volume (GMV) of the (P)FL-complex, GMV of the other cerebellar lobules and GMV of the cerebellar nuclei is investigated in otherwise healthy participants. Data was processed using the SUIT toolbox, which is dedicated to analysis of imaging data of the human cerebellum. GMV of all cerebellar lobules and nuclei were similar between tinnitus and non-tinnitus participants. Moreover, no relation was present between tinnitus severity, as measured by the Tinnitus Handicap Inventory, and (P)FL-complex GMV, tonsil GMV, or total cerebellar cortical GMV. These results suggest that in otherwise healthy participants, in contrast to participants after CPA tumor removal, no relation between the GMV of neither the (P)FL-complex nor other cerebellar lobules and tinnitus presence and severity exists. These findings indicate that a relation only exists when the (P)FL-complex is damaged, for instance by a CPA tumor. Alternatively, it is possible that differences in (P)FL-complex GMVs are too small to detect with a voxel-based morphometry study. Therefore, the role of the (P)FL-complex in tinnitus remains to be further studied

Long-Term Patient-Reported Outcome of Radiofrequency Thalamotomy for Tremor

Background: Thalamotomy is an endorsed treatment for medication-refractory tremor. It used to be the standard, but nowadays deep brain stimulation (DBS) has become the treatment option of choice. Nevertheless, DBS has the disadvantage of hardware failure, battery replacement, and frequent setting adjustment. Radiofrequency (RF) thalamotomy lacks these issues, is relatively inexpensive, and has a broad applicability in patients with significant comorbidity. Therefore, we analyzed the long-term patient-reported outcome of RF thalamotomy in a cohort of patients with an otherwise intractable tremor. Methods: A single-center cohort of 27 consecutive patients with intractable tremor was assessed after unilateral RF thalamotomy. Over time, 4 patients had died because of non-related causes. In total, 21 patients responded to a telephone survey to assess their personal judgment on postoperative tremor severity, using a validated tremor scale, adverse events, recurrence, and patient satisfaction. The median time between surgery and telephone survey was 39 months (range 12-126). Seven patients had an additional analysis with postoperative imaging, video-assisted electromyography tremor registration, and a self-reported treatment effect (SRTE) assessment. Results: Nineteen out of 21 patients (90.5%) reported absence or significant improvement of their tremor. The rating score (WHIGET/UPDRS-III) dropped significantly from a mean of 3.57 preoperatively to 1.05 postoperatively (p < 0.001). Eleven patients (52.4%) reported adverse events, but the majority (76.2%) did not consider the adverse events to be severe. SRTE assessment showed a direct postoperative effect of 89.6 of 100 points (SD 10.8), with a gradual decrease to 75.3 (SD 23.5) during follow-up. Conclusions: RF thalamotomy is a very effective long-term treatment for medication-refractory tremor and should therefore be considered in patients with a refractory unilateral tremor

The influence of transcutaneous electrical neurostimulation (TENS) on human cerebral blood flow velocities

It has been shown that transcutaneous electrical neurostimulation (TENS) reduces sympathetic tone. Spinal cord stimulation (SCS) has proven qualities to improve coronary, peripheral, and cerebral blood circulation. Therefore, we postulate that TENS and SCS affect the autonomic nervous system in analogous ways. In this line of thought, cervical application of TENS might be a useful and simple adjunct in the treatment of cerebrovascular disease by improving cerebral blood flow. Experiments were performed in order to assess whether cervical TENS is safe and whether an effect on cerebral blood flow velocity (CBFV) can be shown in healthy subjects. A controlled, non-randomized, phase 1 study was performed with 20 healthy volunteers. Cervical TENS was applied in several frequencies, with and without hyperventilation. Continuous registration of blood pressure, pulse, CBFV (estimated by transcranial Doppler sonography) and end-tidal carbon dioxide concentration was performed. Cervical TENS was well-tolerated by all subjects. Despite small effects on heart rate (HR) and mean arterial blood pressure (MAP), a significant effect on middle cerebral artery (MCA) blood flow velocity was not demonstrated. No effect of age, gender, current or session order on MCA, HR, or MAP was found. TENS did not influence the effect of hyperventilation. In these experiments, application of cervical TENS is proven to be a safe procedure. However, no effects on cerebral blood flow velocity could be detected, perhaps due to the intact cerebral autoregulation in the healthy volunteers

Patient-Specific Cerebral Blood Flow Simulation Based on Commonly Available Clinical Datasets

Cerebral hemodynamics play an important role in the development of cerebrovascular diseases. In this work, we propose a numerical framework for modeling patient-specific cerebral blood flow, using commonly available clinical datasets. Our hemodynamic model was developed using Simscape Fluids library in Simulink, based on a block diagram language. Medical imaging data obtained from computerized tomography angiography (CTA) in 59 patients with aneurysmal subarachnoid hemorrhage was used to extract arterial geometry parameters. Flow information obtained from transcranial Doppler (TCD) measurement was employed to calibrate input parameters of the hemodynamic model. The results show that the proposed numerical model can reproduce blood flow in the circle of Willis (CoW) per patient per measurement set. The resistance at the distal end of each terminal branch was the predominant parameter for the flow distribution in the CoW. The proposed model may be a promising tool for assessing cerebral hemodynamics in patients with cerebrovascular disease

Study protocol of validating a numerical model to assess the blood flow in the circle of Willis

Introduction We developed a zero-dimensional (0D) model to assess the patient-specific haemodynamics in the circle of Willis (CoW). Similar numerical models for simulating the cerebral blood flow (CBF) had only been validated qualitatively in healthy volunteers by magnetic resonance (MR) angiography and transcranial Doppler (TCD). This study aims to validate whether a numerical model can simulate patient-specific blood flow in the CoW under pathological conditions. Methods and analysis This study is a diagnostic accuracy study. We aim to collect data from a previously performed prospective study that involved patients with aneurysmal subarachnoid haemorrhage (aSAH) receiving both TCD and brain Computerd Tomography angiography (CTA) at the same day. The cerebral flow velocities are calculated by the 0D model, based on the vessel diameters measured on the CTA of each patient. In this study, TCD is considered the gold standard for measuring flow velocity in the CoW. The agreement will be analysed using Pearson correlation coefficients. Ethics and dissemination This study protocol has been approved by the Medical Ethics Review Board of the University Medical Center Groningen: METc2019/103. The results will be submitted to an international scientific journal for peer-reviewed publication. Trial registration number NL8114

Validation of a cerebral hemodynamic model with personalized calibration in patients with aneurysmal subarachnoid hemorrhage

This study aims to validate a numerical model developed for assessing personalized circle of Willis (CoW) hemodynamics under pathological conditions. Based on 66 computed tomography angiography images, investigations were obtained from 43 acute aneurysmal subarachnoid hemorrhage (aSAH) patients from a local neurovascular center. The mean flow velocity of each artery in the CoW measured using transcranial Doppler (TCD) and simulated by the numerical model was obtained for comparison. The intraclass correlation coefficient (ICC) over all cerebral arteries for TCD and the numerical model was 0.88 (N = 561; 95% CI 0.84–0.90). In a subgroup of patients who had developed delayed cerebral ischemia (DCI), the ICC had decreased to 0.72 but remained constant with respect to changes in blood pressure, Fisher grade, and location of ruptured aneurysm. Our numerical model showed good agreement with TCD in assessing the flow velocity in the CoW of patients with aSAH. In conclusion, the proposed model can satisfactorily reproduce the cerebral hemodynamics under aSAH conditions by personalizing the numerical model with TCD measurements. Clinical trial registration: [http://www.trialregister.nl/], identifier [NL8114]