Risk of Thrombus Fragmentation during Endovascular Stroke Treatment.

BACKGROUND AND PURPOSE: Periprocedural thrombus fragmentation is a relevant risk in endovascular stroke treatment. Because factors influencing its occurrence are largely unknown, this study addresses a potential relationship between thrombus histology and clot stability. MATERIALS AND METHODS: Eighty-five patients with anterior circulation stroke treated with thrombectomy were included in this retrospective study. The number and location of emboli after retrieving the primary thrombus, the number of maneuvers, and TICI scores were evaluated. H&E and neutrophil elastase staining of retrieved clots was performed, and semiquantitative measurements of thrombus components were correlated with procedural parameters. RESULTS: An inverse correlation between maneuvers required for thrombus retrieval and the number of distal and intermediate emboli was observed (Spearman r, -0.23; P = .032). Younger patients were at higher risk for periprocedural thrombus fragmentation (Spearman r, -0.23; P = .032). Bridging thrombolysis tended to be associated with fewer maneuvers (2 vs 3, P = .054) but more emboli (1 vs 0, P = .067). While no consistent correlation between procedural parameters and red/white blood cells and fibrin-/platelet fractions could be found, higher amounts of neutrophil elastase-positive cells within the thrombus were independently associated with the occurrence of multiple emboli (adjusted OR, 4.6; 95% CI, 1.1-19.7; P = .041) and lower rates of complete recanalization (adjusted OR, 0.3; 95% CI, 0.1-0.9; P = .050). CONCLUSIONS: Younger age, easy-to-retrieve thrombi, and bridging thrombolysis may be risk factors for periprocedural thrombus fragmentation. Findings from standard histologic stains did not provide insight into thrombectomy-relevant thrombus stability. However, higher neutrophil levels in the thrombus tissue were related to an increased risk of periprocedural thrombus fragmentation. This observation aligns with the proposed thrombolytic capacity of neutrophil elastase and points to its potential clinical relevance in the context of stroke thrombectomy.

The pREset Stent Retriever for Endovascular Treatment of Stroke Caused by MCA Occlusion: Safety and Clinical Outcome.

PURPOSE: The purpose of this study was to analyze the safety and efficacy of the pREset device, a stent retriever system, for endovascular mechanical thrombectomy (MT) in acute ischemic stroke (AIS) after middle cerebral artery (MCA) occlusion. METHODS: Retrospectively, 48 consecutive patients (mean age ± standard deviation, 71.0 ± 11.9 years; 24 women) treated for acute MCA occlusion using pREset solely or in combination with other MT devices were identified. Recanalization success was evaluated using the modified thrombolysis in cerebral infarction score (TICI), and complications were detected by 24-h follow-up computed tomography or magnetic resonance imaging. MCA anatomy was assessed in angiograms. Clinical outcome was evaluated with National Institutes of Health Stroke Scale (NIHSS) score at admission and discharge, and modified Rankin scale (mRS) score at discharge and follow-up. RESULTS: Successful recanalization (TICI 2b/3) was achieved in 39 patients (81.3 %). Rate of procedure-related complications was 8.3 %. In four patients, a subarachnoid hemorrhage occurred (8.3 %), and parenchymal hematoma was detected in four patients (8.3 %). None of those events was associated with clinical deterioration. MCA curvature significantly influenced recanalization success (P < 0.005). Successful recanalization correlated significantly with lower NIHSS scores and favorable clinical outcome (mRS score 0-2) at discharge (P < 0.05). Mortality within 90 days was significantly lower in patients with TICI 2b/3 (P < 0.005). CONCLUSIONS: High recanalization rates, low complication rates, and a significantly improved outcome after successful recanalization strongly suggest that MT with pREset is an adequate therapy for AIS after MCA occlusion. Vessel curvature is a significant determining factor for recanalization success.

Double inversion recovery sequence of the cervical spinal cord in multiple sclerosis and related inflammatory diseases.

BACKGROUND AND PURPOSE: MR imaging plays an important role in diagnosing MS and other related inflammatory diseases; however, imaging of the spinal cord is still challenging. We hypothesized that a 3D double inversion recovery sequence for cervical spinal cord imaging would be more sensitive in detecting inflammatory lesions than a conventional 2D T2-weighted TSE sequence at 3T. MATERIALS AND METHODS: On a 3T MR imaging scanner, we examined 30 patients with suspected or established MS (MS, n = 16; clinically isolated syndrome, n = 12; isolated myelitis, n = 2) and 10 healthy controls. Newly developed 3D double inversion recovery and conventional 2D axial and sagittal T2-weighted TSE images of the cervical spinal cord were acquired. Two blinded neuroradiologists independently assessed the scans in pseudorandomized order for lesion numbers and rated lesion visibility and overall image quality on 5-point scales. A subsequent consensus reading delivered definite lesion counts. Standardized contrast-to-noise ratios were calculated in representative lesions of each patient. RESULTS: Overall, 28% more lesions could be detected with 3D double inversion recovery than with conventional T2WI (119 versus 93, P < .002). On average, the standardized contrast-to-noise ratio was significantly higher (P < .001) in double inversion recovery than in T2WI. Lesion visibility was rated significantly higher (P < .001) in double inversion recovery compared with T2WI despite lower image quality. CONCLUSIONS: The novel 3D double inversion recovery sequence allowed better detection of lesions in MS and related inflammatory diseases of the cervical spinal cord, compared with conventional 2D T2WI.

Disturbed vestibular-neck interaction in cerebellar disease.

Cerebellar dysfunction results in ataxia including postural deficits. Evidence from animal experiments suggests convergence of vestibular and neck-position related inputs in cerebellar midline structures. We investigated 20 ambulatory patients with cerebellar disease for disturbed postural control using posturography during static lateral head turns. Binaural bipolar sine-wave galvanic vestibular stimulation (GVS) was used to evoke specific body movements. The Klockgether clinical score was used to assess the severity of cerebellar dysfunction (4-17 of maximal 35 points). In 12 healthy controls and seven lightly affected patients (score <8), GVS elicited physiologic alternating body sway in the head-frontal plane in seven head-on-trunk positions (0°; 30°, 45° and 60° left and right). Body sway turning with head excursion was progressively attenuated or abolished in more severely affected patients (scores 9-17; r = 0.57, p = 0.008). With most severe impairment, body sway was always in the body-frontal plane irrespective of head turn. A simple clinical test with walking under maximal head turn and closed eyes correlated with posturography data (r = 0.87, p < 0.001) and with Klockgether scores (r = 0.71, p < 0.001). Thus in cerebellar disease, head on trunk position can have a pronounced effect on postural control.

Trunk position influences vestibular responses of fastigial nucleus neurons in the alert monkey.

Vestibulospinal reflexes play an important role for body stabilization during locomotion and for postural control. For an appropriate distribution of vestibular signals to spinal motoneurons, the orientation of the body relative to the head needs to be taken into account. For different trunk positions, identical vestibular stimuli must activate different sets of muscles to ensure body stabilization. Because the cerebellar vermis and the underlying fastigial nucleus (FN) might be involved in this task, vestibular neurons in the rostral FN of alert rhesus monkeys were recorded during sinusoidal vestibular stimulation (0.1-1.0 Hz) in the roll and pitch planes at different trunk-re-head positions (center and +/-45 degrees ). From the sensitivity and phase values measured in these planes, the response properties in the intermediate planes and the stimulus orientation eliciting the optimal response [response vector orientation (RVO)] were calculated. In most neurons, the RVOs rotated systematically with respect to the head, when trunk-re-head position was altered, so that they tended to maintain their orientation with respect to the trunk. Sensitivity and phase at the RVO were not affected. This pattern was the same for neurons in the right and left FN and independent of stimulus frequency. The average sensitivity of this partially compensatory RVO shift in response to trunk-re-head displacements, evaluated by linear regression analyses, was 0.59 degrees / degrees (n = 73 neurons). These data show that FN neurons may encode vestibular information in a coordinate system that is closer to a trunk-centered than to a head-centered reference frame. They indicate an important role of this nucleus in motor programs related to posture and gait control.

Discharge properties of saccade-related neurons in the primate fastigial oculomotor region.

To clarify the mechanisms by which the cerebellar fastigial oculomotor region (FOR) contributes to the control of saccadic eye movements, we recorded saccade-related FOR units in alert monkeys that made horizontal saccades between neighboring points of a three-by-three grid of target positions (16 degrees amplitude). As in previous studies, FOR units exhibited saccade-related bursts that occurred earlier for contralateral than for ipsilateral saccades. In addition, many FOR units reflected variations in the kinematic profiles of the saccades by exhibiting bursts with earlier onset and shorter peak latencies and higher peak discharge rates for fast as compared with slow saccades of the same amplitude. Moreover, reflecting systematic differences in saccade velocity rather than an influence of eye position itself, FOR bursts showed subtle but recurrent and, at the population level, statistically significant differences between centripetal and centrifugal saccades that closely paralleled the eye position dependency of saccadic dysmetria seen after FOR lesions. We conclude that the FOR output signal is not, as previously proposed, specifically related to the temporal properties of the saccade, but also contains information about saccade velocity. Moreover, the FOR output signal appears to change systematically depending on the actual kinematic properties of the saccade, in a way that would help to maintain saccadic accuracy.

Saccade-related neurons in the primate fastigial nucleus: what do they encode?

The cerebellar fastigial oculomotor region (FOR) and the overlying oculomotor vermis (OV) are involved in the control of saccadic eye movements, but nature and function of their saccade-related neuronal signals are not fully understood. There is controversy in at least two major aspects: first, lesion studies in OV/FOR reported eye-position-dependent dysmetria-with FOR lesions, centripetal saccades became more hypermetric than centrifugal saccades-suggesting that the cerebellum may compensate for orbital mechanics. However, single-unit studies failed to reveal corresponding eye-position dependencies in FOR saccade-related discharge patterns. Second, some single-unit studies reported precise correlation between burst and saccade duration in the FOR. However, others stated that FOR bursts were only weakly related to saccade properties. In an attempt to resolve these discrepancies, we recorded single FOR units in monkeys that made horizontal saccades (16 degrees ) from different starting positions. Sampling saccades of one fixed amplitude and application of an objective, computer-based burst-detection-routine allowed us to correlate burst parameters (onset latency, peak latency, peak amplitude, number of spikes, duration) and kinematic properties of individual saccades. FOR bursts were found to start and peak earlier and exhibit higher peak burst amplitudes for faster than for slower saccades of the same amplitude. While these correlations between FOR bursts and saccade properties were statistically significant for a minority of approximately 20-25% of individual units, the same effects were also predominant in the remainder of the neuronal sample and statistically significant on the population level. Neuronal activity was not significantly modulated by eye position itself. However, reflecting differences in saccade velocities but not an actual influence of eye position per se, FOR bursts for centripetal and centrifugal saccades exhibited subtle but systematic differences, which closely paralleled, and hence probably explain, the eye-position dependency of deficits observed after FOR inactivation. Our findings indicate that FOR signals reflect much of the kinematic properties of the saccade. Moreover, they are consistent with the idea that the FOR output is purposefully modified according to these kinematic properties to maintain saccadic accuracy.

Canal-otolith interaction in the fastigial nucleus of the alert monkey.

To determine the contribution of the otoliths as well as the horizontal and vertical semicircular canals to the response of "vestibular only" neurons in the rostral fastigial nucleus of the alert monkey, we applied natural sinusoidal vestibular stimuli (0.6 Hz; +/-15 deg) around different axes. During the experiment the monkey sat erect in a primate chair with the head immobile. Semicircular canal responses were investigated during tilted yaw stimulation around an earth vertical axis. The tilt angle was varied by 30 deg and included the optimal plane for horizontal canal stimulation (15 deg nose down from the stereotactic plane). The otoliths and mainly the vertical canals made contributions during stimulation around an earth-fixed horizontal axis (vertical stimulation). Head orientation was also slowly altered (2-3 deg/s) over a range of 180 deg under both stimulus conditions (tilted yaw and vertical stimulation). Neuronal data for each paradigm were fitted by a least squares best-sine function. Computation of the hypothetical contributions made by all three pairs of semicircular canals and the otoliths to these responses showed that 74% of the 46 neurons investigated received an otolith input; in most instances it was combined with a canal input. Neurons most often received input from the horizontal and vertical canals as well as the otoliths. Only a minority of neurons received a purely otolith (13%), vertical canal (13%), or horizontal canal (4%) input. Conventional criteria (head position-related activity, spatiotemporal convergence, STC) failed to detect an otolith contribution in several such instances. Thus, canal-otolith convergence is the general rule at this central stage of vestibular information processing in the fastigial nucleus. The large variety of response types allows these neurons to participate in multiple tasks of vestibulospinal movement control.

Fastigial nucleus activity during different frequencies and orientations of vertical vestibular stimulation in the monkey.

Neurons in the rostral part of the fastigial nucleus (FN) respond to vestibular stimulation but are not related to eye movements. To understand the precise role of these vestibular-only neurons in the central processing of vestibular signals, unit activity in the FN of alert monkeys (Macaca mulatta) was recorded. To induce vestibular stimulation, the monkey was rotated sinusoidally around an earth-fixed horizontal axis at stimulus frequencies between 0.06 (+/-15 degrees) and 1.4 Hz (+/-7.5 degrees). During stimulation head orientation was changed continuously, allowing for roll, pitch, and intermediate planes of orientation. At a frequency of 0.6 Hz, 59% of the neurons had an optimal response orientation (ORO) and a null response (i.e., no modulation) 90 degrees apart. The phase of neuronal response was constant except for a steep shift of 180 degrees around the null response. This group I response is compatible with a semicircular canal input, canal convergence, or a single otolith input. Several other features indicated more complex responses, including spatiotemporal convergence (STC). 1) For 35% of the responses at 0.6 Hz, phase changes were gradual with different orientations. Fifteen percent of these had a null response (group II), and 20% showed only a minimal response but no null response (group III). The remaining responses (6%), classified as group IV, were characterized by a constant sensitivity at different orientations in most instances. 2) For the vast majority of neurons, the stimulus frequency determined the response group, i.e., an individual neuron could show a group I response at one frequency and a group II (III or IV) response at another frequency. 3) ORO changed with frequency by >45 degrees for 44% of the neurons. 4) Although phase changes at different frequencies were close to head velocity (+/-45 degrees ) or head position (+/-45 degrees ) for most neurons, they exceeded 90 degrees for 29% of the neurons between 0.1 and 1.0 Hz. In most cases, this was a phase advance. The change in sensitivity with change in frequency showed a similar pattern for all neurons; the average sensitivity increased from 1.24 imp. s-1. deg-1 at 0.1 Hz to 2.97 imp. s-1. deg-1 at 1.0 Hz. These data demonstrate that only an analysis based on measurements at different frequencies and orientations reveals a number of complex features. They moreover suggest that for the vast majority of neurons several sources of canal and otolith information interact at this central stage of vestibular information processing.

Otolith processing in the deep cerebellar nuclei.

To investigate the otolith contribution to the responses of "vestibular only" neurons in the rostral fastigial nucleus (FN), single-unit activity was recorded in the alert monkey with the head fixed during static and dynamic stimulation (+/- 15 deg, 0.06-1.4 Hz) around an earth-fixed horizontal axis. Head orientation could be altered allowing for roll, pitch, and intermediate planes of orientation. For the vast majority of neurons a response vector orientation (RVO) with an optimal response and a null-response at a head orientation 90 deg apart could be determined. Presumably more than 30% of the vestibular only neurons had an otolith input, as indicated by responses to static tilt, head-position-related activity, large phase changes (> 100 deg) of neuronal activity between 0.06 and 1.4 Hz, changes of the RVO at different frequencies and complex responses (spatio-temporal convergence). Thus, neurons in FN reflecting an otolith or a combined canal-otolith input are much more common than up to now thought. Vestibular-only neurons are most likely involved in vestibulospinal mechanisms. Their precise functional role has yet to be determined.

Cortical areas activated by bilateral galvanic vestibular stimulation.

The brain areas activated by bilateral galvanic vestibular stimulation (GVS) were studied using functional magnetic resonance imaging. In six human volunteers, GVS led to activation in the region of the temporoparietal junction, the central sulcus, and the anterior interior intraparietal sulcus, which may correspond to macaque areas PIVC, 3aV, and 2v, respectively. In addition, activation was found in premotor regions of the frontal lobe, presumably analogous to areas 6pa and 8a in the monkey. Since these areas were not detected in previous studies using caloric vestibular stimulation, they could be related to the modulation of otolith afferent activity by GVS. However, the simple paradigm used did not allow separation of the otolithic and semicircular canal effects of GVS. Further studies must be performed to clarify the question of cortical representation of the otolithic information in the human and monkey brain.

Variable otolith contribution to the galvanically induced vestibulo-ocular reflex.

The torsional eye movements elicited by sinusoidal galvanic vestibular stimulation (GVS) (0.012-3.13 Hz) were examined in healthy humans. GVS consistently induced sinusoidal modulation of the torsional slow phase velocity (SPV), which was linearly related to stimulus intensity. At low frequencies (< 0.1 Hz) nystagmic responses could be discriminated from an underlying 'tonic' modulation of eye position, which was prominent in some, but negligible in other subjects, and was not correlated with the SPV modulation. The actual SPV modulation consistently exceeded the (hypothetical) velocity modulation derived from the tonic positional components, albeit variably by almost 20-fold across subjects. This indicates that the contribution of possibly otolith-related response components to the galvanic vestibulo-ocular reflex may vary considerably in normal individuals.

Linear spatio-temporal convergence in vestibular neurons of the primate nucleus fastigii.

Vestibular responses in the primate fastigial nucleus (FN) do often not follow the simple cosine tuning observed in primary vestibular afferents. The present report demonstrates that these more complex patterns can mostly be attributed to simple linear summation of spatially and temporally diverse cosine-tuned input signals (linear spatio-temporal convergence, STC). Analyses following from this elementary finding, however, reveal frequency-dependent properties in many FN neurons, which are difficult to reconcile with existing concepts of possible functions of STC in central vestibular areas. The demonstration that STC linearity holds for FN responses is thus of both theoretical and practical relevance, allowing shortening of future experimental protocols and facilitating comparison of the observed spatio-temporal response dynamics with those at other stages of vestibular signal processing.

Functional MRI of galvanic vestibular stimulation.

The cortical processing of vestibular information is not hierarchically organized as the processing of signals in the visual and auditory modalities. Anatomic and electrophysiological studies in the monkey revealed the existence of multiple interconnected areas in which vestibular signals converge with visual and/or somatosensory inputs. Although recent functional imaging studies using caloric vestibular stimulation (CVS) suggest that vestibular signals in the human cerebral cortex may be similarly distributed, some areas that apparently form essential constituents of the monkey cortical vestibular system have not yet been identified in humans. Galvanic vestibular stimulation (GVS) has been used for almost 200 years for the exploration of the vestibular system. By contrast with CVS, which mediates its effects mainly via the semicircular canals (SCC), GVS has been shown to act equally on SCC and otolith afferents. Because galvanic stimuli can be controlled precisely, GVS is suited ideally for the investigation of the vestibular cortex by means of functional imaging techniques. We studied the brain areas activated by sinusoidal GVS using functional magnetic resonance imaging (fMRI). An adapted set-up including LC filters tuned for resonance at the Larmor frequency protected the volunteers against burns through radio-frequency pickup by the stimulation electrodes. Control experiments ensured that potentially harmful effects or degradation of the functional images did not occur. Six male, right-handed volunteers participated in the study. In all of them, GVS induced clear perceptions of body movement and moderate cutaneous sensations at the electrode sites. Comparison with anatomic data on the primate cortical vestibular system and with imaging studies using somatosensory stimulation indicated that most activation foci could be related to the vestibular component of the stimulus. Activation appeared in the region of the temporo-parietal junction, the central sulcus, and the intraparietal sulcus. These areas may be analogous to areas PIVC, 3aV, and 2v, respectively, which form in the monkey brain, the "inner vestibular circle". Activation also occurred in premotor regions of the frontal lobe. Although undetected in previous imaging-studies using CVS, involvement of these areas could be predicted from anatomic data showing projections from the anterior ventral part of area 6 to the inner vestibular circle and the vestibular nuclei. Using a simple paradigm, we showed that GVS can be implemented safely in the fMRI environment. Manipulating stimulus waveforms and thus the GVS-induced subjective vestibular sensations in future imaging studies may yield further insights into the cortical processing of vestibular signals.