Intracranial angioleiomyoma: a case series of seven patients and review of the literature.

PURPOSE: Angioleiomyoma, predominantly arising from the extremities, is a benign soft tissue tumor. Reports on its intracranial location are rare. We assessed clinical, radiological, and pathological features of intracranial angioleiomyoma (iALM) treated at our neurosurgical institution. METHODS: We consecutively enrolled all patients with neuropathologically confirmed iALM treated at a single neurosurgical institution between 2013 and 2021. Clinical and imaging data were collected, and histological tissue sections were analyzed. A review of the literature on iALM was conducted. RESULTS: Seven patients with iALM (four female) with a median age of 45 years (range: 32-76 years) were identified. In three cases, the lesion was found incidentally. In magnetic resonance imaging (MRI), all tumors were hypo- to isointense on T1-weighted, hyperintense on T2-weighted sequences, and gadolinium-enhancing. A strong FLAIR signal was seen in six patients. Surgery consisted of gross total resection in all cases without perioperative complications. Neuropathological staining was positive for smooth muscle actin (SMA) in all lesions. Mature smooth muscle cells arranged around blood vessels were typically observed. The Ki-67 index was ≤ 3%. The patients were discharged after a median of 6 days (range: 4-9 days). During a median follow-up time of 14 months (range: 4-41 months), no tumor recurrence occurred. In the current literature, 42 additional cases of iALM were identified. CONCLUSION: Intracranial angioleiomyoma is a benign soft tissue tumor treated by gross total resection. Tumor morphology and positive staining for SMA lead to the neuropathological diagnosis.

MRI in LARS1 deficiency-Spectrum, patterns, and correlation with acute neurological deterioration.

Leucine aminoacyl tRNA-synthetase 1 (LARS1)-deficiency (infantile liver failure syndrome type 1 (ILFS1)) has a multisystemic phenotype including fever-associated acute liver failure (ALF), chronic neurologic abnormalities, and encephalopathic episodes. In order to better characterize encephalopathic episodes and MRI changes, 35 cranial MRIs from 13 individuals with LARS1 deficiency were systematically assessed and neurological phenotype was analyzed. All individuals had developmental delay and 10/13 had seizures. Encephalopathic episodes in 8/13 were typically associated with infections, presented with seizures and reduced consciousness, mostly accompanied by hepatic dysfunction, and recovery in 17/19 episodes. Encephalopathy without hepatic dysfunction occurred in one individual after liver transplantation. On MRI, 5/7 individuals with MRI during acute encephalopathy had deep gray matter and brainstem changes. Supratentorial cortex involvement (6/13) and cerebellar watershed injury (4/13) occurred with seizures and/or encephalopathy. Abnormal brainstem contour on sagittal images (8/13), atrophy (8/13), and myelination delay (8/13) were not clearly associated with encephalopathy. The pattern of deep gray matter and brainstem changes are apparently characteristic of encephalopathy in LARS1-deficiency, differing from patterns of hepatic encephalopathy or metabolic stroke in organic acidurias and mitochondrial diseases. While the pathomechanism remains unclear, fever and energy deficit during infections might be causative; thus, sufficient glucose and protein intake along with pro-active fever management is suggested. As severe episodes were observed during influenza infections, we strongly recommend seasonal vaccination.

Orthogonal Peptide-Templated Labeling Elucidates Lateral ETA R/ETB R Proximity and Reveals Altered Downstream Signaling.

Fine-tuning of G protein-coupled receptor (GPCR) signaling is important to maintain cellular homeostasis. Recent studies demonstrated that lateral GPCR interactions in the cell membrane can impact signaling profiles. Here, we report on a one-step labeling method of multiple membrane-embedded GPCRs. Based on short peptide tags, complementary probes transfer the cargo (e. g. a fluorescent dye) by an acyl transfer reaction with high spatial and temporal resolution within 5 min. We applied this approach to four receptors of the cardiovascular system: the endothelin receptor A and B (ETA R and ETB R), angiotensin II receptor type 1, and apelin. Wild type-like G protein activation after N-terminal modification was demonstrated for all receptor species. Using FRET-competent dyes, a constitutive proximity between hetero-receptors was limited to ETA R/ETB R. Further, we demonstrate, that ETA R expression regulates the signaling of co-expressed ETB R. Our orthogonal peptide-templated labeling of different GPCRs provides novel insight into the regulation of GPCR signaling.

Subdural hematoma in glutaric aciduria type 1: High excreters are prone to incidental SDH despite newborn screening.

Subdural hematoma (SDH) was initially reported in 20% to 30% of patients with glutaric aciduria type 1 (GA1). A recent retrospective study found SDH in 4% of patients, but not in patients identified by newborn screening (NBS). 168 MRIs of 69 patients with GA1 (age at MRI 9 days - 73.8 years, median 3.2 years) were systematically reviewed for presence of SDH, additional MR and clinical findings in order to investigate the frequency of SDH and potential risk factors. SDH was observed in eight high-excreting patients imaged between 5.8 and 24.4 months, namely space-occupying SDH in two patients after minor accidental trauma and SDH as an incidental finding in six patients without trauma. In patients without trauma imaged at 3 to 30 months (n = 36, 25 NBS, 27/9 high/low excreters), incidence of SDH was 16.7% (16% in NBS). SDH was more common after acute (33.3%) than insidious onset of dystonia (14.3%) or in asymptomatic patients (5.9%). It was only seen in patients with wide frontoparietal CSF spaces and frontotemporal hypoplasia. High excreters were over-represented among patients with SDH (6/27 vs 0/9 low excreters), acute onset (10/12), and wide frontoparietal CSF spaces (16/19). Incidental SDH occurs despite NBS and early treatment in approximately one in six patients with GA1 imaged during late infancy and early childhood. Greater risk of high excreters is morphologically associated with more frequent enlargement of external CSF spaces including frontotemporal hypoplasia, and may be furthered aggravated by more pronounced alterations of cerebral blood volume and venous pressure.

Brain MR patterns in inherited disorders of monoamine neurotransmitters: An analysis of 70 patients.

Inherited monoamine neurotransmitter disorders (iMNDs) are rare disorders with clinical manifestations ranging from mild infantile hypotonia, movement disorders to early infantile severe encephalopathy. Neuroimaging has been reported as non-specific. We systematically analyzed brain MRIs in order to characterize and better understand neuroimaging changes and to re-evaluate the diagnostic role of brain MRI in iMNDs. 81 MRIs of 70 patients (0.1-52.9 years, 39 patients with tetrahydrobiopterin deficiencies, 31 with primary disorders of monoamine metabolism) were retrospectively analyzed and clinical records reviewed. 33/70 patients had MRI changes, most commonly atrophy (n = 24). Eight patients, six with dihydropteridine reductase deficiency (DHPR), had a common pattern of bilateral parieto-occipital and to a lesser extent frontal and/or cerebellar changes in arterial watershed zones. Two patients imaged after acute severe encephalopathy had signs of profound hypoxic-ischemic injury and a combination of deep gray matter and watershed injury (aromatic l-amino acid decarboxylase (AADCD), tyrosine hydroxylase deficiency (THD)). Four patients had myelination delay (AADCD; THD); two had changes characteristic of post-infantile onset neuronal disease (AADCD, monoamine oxidase A deficiency), and nine T2-hyperintensity of central tegmental tracts. iMNDs are associated with MRI patterns consistent with chronic effects of a neuronal disorder and signs of repetitive injury to cerebral and cerebellar watershed areas, in particular in DHPRD. These will be helpful in the (neuroradiological) differential diagnosis of children with unknown disorders and monitoring of iMNDs. We hypothesize that deficiency of catecholamines and/or tetrahydrobiopterin increase the incidence of and the CNS susceptibility to vascular dysfunction.

Impact of a new metal artefact reduction algorithm in the noninvasive follow-up of intracranial clips, coils, and stents with flat-panel angiographic CTA: initial results.

INTRODUCTION: Flat-panel angiographic CT after intravenous contrast agent application (ivACT) is increasingly used as a follow-up examination after coiling, clipping, or stenting. The purpose of this study was to evaluate the feasibility of a new metal artefact reduction algorithm (MARA) in patients treated for intracranial aneurysms and stenosis. METHODS: IvACT was performed on a flat-panel detector angiography system after intravenous application of 80 ml contrast media. The uncorrected raw images were transferred to a prototype reconstruction workstation where the MARA was applied. Two experienced neuroradiologists examined the corrected and uncorrected images on a commercially available workstation. RESULTS: Artefacts around the implants were detected in all 16 uncorrected cases, while eight cases showed remaining artefacts after correction with the MARA. In the cases without correction, there were 11 cases with "extensive" artefacts and five cases with "many" artefacts. After correction, seven cases showed "few" and only one case "many" artefacts (Wilcoxon test, P < 0.001). Parent vessels were characterized as "not identifiable" in 62% of uncorrected images, while the delineation of parent vessels were classified as "excellent" in 50% of the cases after correction (Wilcoxon test, P = 0.001). CONCLUSIONS: Use of the MARA in our study significantly reduced artefacts around metallic implants on ivACT images and allowed for the delineation of surrounding structures.

A de novo interstitial deletion of 2p23.3-24.3 in a boy presenting with intellectual disability, overgrowth, dysmorphic features, skeletal myopathy, dilated cardiomyopathy.

Interstitial deletions of the distal part of chromosome 2p are rare, with only six reported cases involving regions from 2p23 to 2pter. Most of these were cytogenetic investigations. We describe a 14-year-old boy with an 8.97 Mb deletion of 2p23.3-24.3 detected by array comparative genomic hybridization (array CGH) who had intellectual disability (ID), unusual facial features, cryptorchidism, skeletal myopathy, dilated cardiomyopathy (DCM), and postnatal overgrowth (macrocephaly and tall stature). We compared the clinical features of the present case to previously described patients with an interstitial deletion within this chromosomal region and conclude that our patient exhibits a markedly different phenotype. Additional patients are needed to further delineate phenotype-genotype correlations.

Necrotizing infundibulo-hypophysitis: an entity too rare to be true?

We report a young woman with sudden and severe retroorbital headache, neck pain, and a large sellar mass extending to the suprasellar cistern. A presumptive diagnosis of non-secreting pituitary macroadenoma undergoing apoplexy was made and transphenoidal surgery performed. Histopathology revealed mononuclear infiltration and marked non-hemorrhagic necrosis of the anterior pituitary consistent with a diagnosis of necrotizing infundibulo-hypophysitis. The possible pathogenesis of this rare variant of hypophysitis is discussed.

Identification of PMD subgroups using a myelination score for PMD.

BACKGROUND: The clinical spectrum of Pelizaeus-Merzbacher disease (PMD), a common hypomyelinating leukodystrophy, ranges between severe neonatal onset and a relatively stable presentation with later onset and mainly lower limb spasticity. In view of emerging treatment options and in order to grade severity and progression, we developed a PMD myelination score. METHODS: Myelination was scored in 15 anatomic sites (items) on conventional T2-and T1w images in controls (n = 328) and 28 PMD patients (53 MRI; n = 5 connatal, n = 3 transitional, n = 10 classic, n = 3 intermediate, n = 2 PLP0, n = 3 SPG2, n = 2 female). Items included in the score were selected based on interrater variability, practicability of scoring and importance of scoring items for discrimination between patients and controls and between patient subgroups. Bicaudate ratio, maximal sagittal pons diameter, and visual assessment of midsagittal corpus callosum were separately recorded. RESULTS: The resulting myelination score consisting of 8 T2-and 5 T1-items differentiates patients and controls as well as patient subgroups at first MRI. There was very little myelin and early loss in severely affected connatal and transitional patients, more, though still severely deficient myelin in classic PMD, ongoing myelination during childhood in classic and intermediate PMD. Atrophy, present in 50% of patients, increased with age at imaging. CONCLUSIONS: The proposed myelination score allows stratification of PMD patients and standardized assessment of follow-up. Loss of myelin in severely affected and PLP0 patients and progressing myelination in classic and intermediate PMD must be considered when evaluating treatment efficacy.

Individual voxel-based subtype prediction can differentiate progressive supranuclear palsy from idiopathic Parkinson syndrome and healthy controls.

Voxel-based morphometry (VBM) shows a differentiated pattern in patients with atypical Parkinson syndrome but so far has had little impact in individual cases. It is desirable to translate VBM findings into clinical practice and individual classification. To this end, we examined whether a support vector machine (SVM) can provide useful accuracies for the differential diagnosis. We acquired a volumetric 3D T1-weighted MRI of 21 patients with idiopathic Parkinson syndrome (IPS), 11 multiple systems atrophy (MSA-P) and 10 progressive supranuclear palsy (PSP), and 22 healthy controls. Images were segmented, normalized, and compared at group level with SPM8 in a classical VBM design. Next, a SVM analysis was performed on an individual basis with leave-one-out cross-validation. VBM showed a strong white matter loss in the mesencephalon of patients with PSP, a putaminal grey matter loss in MSA, and a cerebellar grey matter loss in patients with PSP compared with IPS. The SVM allowed for an individual classification in PSP versus IPS with up to 96.8% accuracy with 90% sensitivity and 100% specificity. In MSA versus IPS, an accuracy of 71.9% was achieved; sensitivity, however, was low with 36.4%. Patients with IPS could not be differentiated from controls. In summary, a voxel-based SVM analysis allows for a reliable classification of individual cases in PSP that can be directly clinically useful. For patients with MSA and IPS, further developments like quantitative MRI are needed.

Comparing different MR angiography strategies of carotid stents in a vascular flow model: toward stent-specific recommendations in MR follow-up.

INTRODUCTION: Carotid artery stenting (CAS) requires adequate follow-up imaging to assess complications such as in-stent stenosis or occlusion. Options include digital subtraction angiography, CT angiography, ultrasound, and MR angiography (MRA), which may offer a non-invasive option for CAS follow-up imaging. The aim of this study was to assess contrast-enhanced MRA (CE-MRA) and three-dimensional time-of-flight MRA (3D-TOF) for visualization of the in-stent lumen in different carotid stents. METHODS: In this study, we compared CE-MRA and 3D-TOF of five different carotid stents (Guidant Acculink®, Cordis Precise®, Boston Wallstent®, Abbot Vascular Xact®, Cook Zilver®) in three diameters (4, 6, and 8 mm) using a vascular flow model at 3.0 T with the help of a recently developed carotid surface coil. Stent-related artifacts were objectively assessed by calculating artificial lumen narrowing (ALN) and relative in-stent signal (RIS). RESULTS: RIS and ALN depended heavily on stent type, stent diameter, and the employed MR sequence. ALN and RIS were relatively favorable for Acculink®, Precise®, and Zilver® stents with both CE-MRA and 3D-TOF. CE-MRA provided better results for the Wallstent, while the Xact stent was difficult to visualize with both MRA protocols. CONCLUSION: Both CE-MRA and 3D-TOF are viable options for depicting the in-stent lumen in carotid stents. For specific stents, 3D-TOF provided image quality comparable to CE-MRA and may thus be suitable for in vivo assessment. Development of stent-specific pathways for follow-up imaging seems advisable to address stent-related differences in image quality.

Polymicrogyria in fetal alcohol syndrome.

BACKGROUND: Intrauterine exposure to alcohol may result in a distinct pattern of craniofacial abnormalities and central nervous system dysfunction, designated fetal alcohol syndrome (FAS). The spectrum of malformations of the brain associated with maternal alcohol abuse during pregnancy is much broader than the relatively uniform clinical phenotype of FAS. Among these malformations the most striking abnormalities involve the impairment of neuronal cell migration. However, polymicrogyria (PMG) has so far been reported only once in a human autopsy study of a child with FAS. CASE: A 16-year-old girl with confirmed maternal alcohol consumption during pregnancy and full phenotype of FAS presented after two generalized epileptic seizures for neurologic assessment. Cranial magnetic resonance imaging revealed bilateral PMG in the superior frontal gyrus with asymmetric distribution. History, clinical features, and genetic investigations provided no evidence for any of the known genetic or acquired causes of PMG. Therefore, we propose that prenatal alcohol exposure is the cause of PMG in this patient rather than a mere coincidence. CONCLUSION: Our observation represents only the second patient of PMG in FAS and confirms the phenotypic variability of cerebral malformations associated with maternal alcohol abuse during pregnancy. In patients with clinical features of FAS and neurologic deficits or seizures neuroimaging is recommended. Furthermore, FAS should be considered as a differential diagnosis for PMG.

Evaluation of angiographic computed tomography in the follow-up after endovascular treatment of cerebral aneurysms--a comparative study with DSA and TOF-MRA.

Following coil embolization of intracranial aneurysms, many centers perform at least one digital subtraction angiography (DSA) continuing with time-of-flight magnetic resonance angiography (TOF-MRA). Angiographic computed tomography (ACT) provides high-resolution data from a rotational acquisition of a c-arm-mounted flat panel detector. This study evaluates possible advantages of applying ACT in aneurysm follow-up. In 22 patients DSA examinations with a rotational acquisition were performed. Rotational data were processed into an isotropic high-resolution volume. TOF-MRA was performed the day before DSA. Three experienced neuroradiologists performed a rating of the occlusion rate and a subjective method comparison. Weighted kappa statistics were calculated to assess the level of interobserver agreement. Compared to DSA, the diagnostic value of ACT as well as of TOF-MRA was rated to be inferior, although the sensitivity of detecting residual necks was higher with both techniques. Compared to TOF-MRA, ACT achieves favorable ratings only in aneurysms after stent-remodeling. Interobserver agreement was high for all techniques. Ratings of the occlusion rate correlated highly between all observers (r>0.85, p<0.001, respectively). In selected patients ACT can add valuable diagnostic information to DSA. TOF-MRA remains a highly sensitive method for aneurysm follow-up.

Modulation of the neural network involved in the processing of anger prosody: the role of task-relevance and social phobia.

Individuals with social phobia display neural hyperactivation towards angry facial expressions. However, it is uncertain whether they also show abnormal brain responses when processing angry voices. In an event-related functional magnetic resonance imaging study, we investigated brain responses to neutral and angry voices in 12 healthy control participants and 12 individuals with social phobia when emotional prosody was either task-relevant or task-irrelevant. Regardless of task, both phobic and non-phobic participants recruited a network comprising frontotemporal regions, the amygdala, the insula, and the striatum, when listening to angry compared to neutral prosody. Across participants, increased activation in orbitofrontal cortex during task-relevant as compared to task-irrelevant emotional prosody processing was found. Compared to healthy controls, individuals with social phobia displayed significantly stronger orbitofrontal activation in response to angry versus neutral voices under both task conditions. These results suggest a disorder-associated increased involvement of the orbitofrontal cortex in response to threatening voices in social phobia.

Magnetic resonance imaging evidence of cytotoxic cerebral edema in acute mountain sickness.

The present study applied T2- and diffusion-weighted magnetic resonance imaging to examine if mild cerebral edema and subsequent brain swelling are implicated in the pathophysiology of acute mountain sickness (AMS). Twenty-two subjects were examined in normoxia (21% O2), after 16 hours passive exposure to normobaric hypoxia (12% O2) corresponding to a simulated altitude of 4,500 m and after 6 hours recovery in normoxia. Clinical AMS was diagnosed in 50% of subjects during hypoxia and corresponding headache scores were markedly elevated (P<0.05 versus non-AMS). Hypoxia was associated with a mild increase in brain volume (+7.0+/-4.8 ml, P<0.05 versus pre-exposure baseline) that resolved during normoxic recovery. Hypoxia was also associated with an increased T2 relaxation time (T2rt) and a general trend toward an increased apparent diffusion coefficient (ADC). During the normoxic recovery, brain volume and T2rt recovered to pre-exposure baseline values, whereas a more marked reduction in ADC in the splenium of the corpus callosum (SCC) was observed (P<0.05). While changes in brain volume and T2rt were not selectively different in AMS, ADC values were consistently lower (P<0.05 versus non-AMS) and associated with the severity of neurologic symptoms. Acute mountain sickness was also characterized by an increased brain to intracranial volume ratio (P<0.05 versus non-AMS). These findings indicate that mild extracellular vasogenic edema contributes to the generalized brain swelling observed at high altitude, independent of AMS. In contrast, intracellular cytotoxic edema combined with an anatomic predisposition to a 'tight-fit' brain may prove of pathophysiologic significance, although the increase in brain volume in hypoxia was only about 0.5% of total brain volume.

T2*-weighted MRI in diagnosis of multiple system atrophy. A practical approach for clinicians.

BACKGROUND: Putaminal iron deposition is a histopathological feature of multiple system atrophy (MSA), which is not observed in patients with idiopathic Parkinson's disease (PD). T2*-weighted magnetic resonance imaging (MRI) gradient echo (GE) sequences are sensitive for paramagnetic susceptibility changes and therefore may support the clinical differential diagnosis between MSA and PD. METHODS: We evaluated putaminal signal intensities on 1.0 Tesla scans of 52 MSA patients, 88 patients with PD and 29 healthy control subjects. RESULTS: The typical finding in T2* GE sequences of MSA patients was a signal loss of the dorsolateral putamen, which showed a high specificity (>0.91), but was present in only a subpopulation of patients (sensitivity 0.64-0.69). The combination of the latter with additional presence of a hyperintense lateral rim in fluid attenuated inversion recovery (FLAIR) sequences increased the specificity to 0.97. Using a quantitative evaluation of putaminal signal intensities in defined regions of interest MSA and PD could be discriminated with a diagnostic accuracy (r) of up to 0.82. CONCLUSION: Although the separation of groups remains incomplete, the use of T2*-weighted GE sequences combined with FLAIR may be helpful for the differential diagnosis of MSA versus PD considering its fast application, easy evaluation, broad availability, the specificity of findings and the presence of putaminal signal loss already at early disease stages.

Recognition and evaluation of emotional prosody in individuals with generalized social phobia: a pilot study.

Studies using facial emotional expressions as stimuli partially support the assumption of biased processing of social signals in social phobia. This pilot study explored for the first time whether individuals with social phobia display a processing bias towards emotional prosody. Fifteen individuals with generalized social phobia and fifteen healthy controls (HC) matched for gender, age, and education completed a recognition test consisting of meaningless utterances spoken in a neutral, angry, sad, fearful, disgusted or happy tone of voice. Participants also evaluated the stimuli with regard to valence and arousal. While these ratings did not differ significantly between groups, analysis of the recognition test revealed enhanced identification of sad and fearful voices and decreased identification of happy voices in individuals with social phobia compared with HC. The two groups did not differ in their processing of neutral, disgust, and anger prosody.

Transcranial color-coded duplex sonography in suspected acute basilar artery occlusion.

Transcranial color-coded duplex sonography (TCDS) is a noninvasive, quick and inexpensive diagnostic tool used routinely to assess vascular abnormalities in cerebral ischemia. The value of TCDS for diagnosis and follow-up of acute basilar artery (BA) ischemia in comparison/combination with spiral CT angiography (CTA) and/or digital subtraction angiography (DSA) has not yet been studied. We prospectively studied 15 consecutive patients with clinically suspected acute BA occlusion (BAO) by TCDS as well as 3 to 5 d later in those with proven BAO. BA ischemia was verified in 11 patients. During follow-up, all BAO patients showed recanalization of the BA independent of thrombolytic treatment. In conclusion, TCDS appears to be an efficient method for BAO diagnosis when immediate angiography is not available. Together with CTA it increases diagnostic safety before performing an invasive and cost-intensive DSA.

MR imaging-based volumetry in patients with early-treated phenylketonuria.

BACKGROUND AND PURPOSE: Our purpose was to specify the most severely affected brain structures in early treated phenylketonuria regarding volume loss and establish possible correlations between volume loss and plasma levels of phenylalanine (Phe). METHODS: In 31 patients with early treated phenylketonuria and in 27 healthy volunteers, we acquired volumetric MR imaging data. Serum Phe concentrations at different times were measured as well. Semiautomatic volumetric postprocessing of the cerebellum, cerebrum (supratentorial brain tissue), hippocampus, intracranial volume, lateral ventricles, nucleus caudatus, nucleus lentiformis, pons, and thalamus, as well as the two-dimensional extension of the corpus callosum, was performed using the software BRAINS2. For each separate brain structure, the relative differences between the normal and the phenylketonuria group (delta(rel)) were calculated. RESULTS: The cerebrum, corpus callosum, hippocampus, intracranial volume, and pons were significantly smaller in patients with phenylketonuria than in healthy patients. The volume of the lateral ventricles was significantly larger in patients with phenylketonuria than in healthy ones. The most severely affected structures were the pons (delta(rel) = 16%), hippocampus (delta(rel) = 14.5%), cerebrum (delta(rel) = 13%), and corpus callosum (delta(rel) = 10%). No significant differences were found for the basal ganglia, cerebellum, and thalamus. There were no significant correlations found between the volume of any of the different brain structures and the metabolic parameters. CONCLUSION: The most severely affected brain structures in early-treated patients with phenylketonuria regarding volume loss are the cerebrum, corpus callosum, hippocampus, and pons.