Metastable dynamics of neural circuits and networks.

Cortical neurons emit seemingly erratic trains of action potentials or "spikes," and neural network dynamics emerge from the coordinated spiking activity within neural circuits. These rich dynamics manifest themselves in a variety of patterns, which emerge spontaneously or in response to incoming activity produced by sensory inputs. In this Review, we focus on neural dynamics that is best understood as a sequence of repeated activations of a number of discrete hidden states. These transiently occupied states are termed "metastable" and have been linked to important sensory and cognitive functions. In the rodent gustatory cortex, for instance, metastable dynamics have been associated with stimulus coding, with states of expectation, and with decision making. In frontal, parietal, and motor areas of macaques, metastable activity has been related to behavioral performance, choice behavior, task difficulty, and attention. In this article, we review the experimental evidence for neural metastable dynamics together with theoretical approaches to the study of metastable activity in neural circuits. These approaches include (i) a theoretical framework based on non-equilibrium statistical physics for network dynamics; (ii) statistical approaches to extract information about metastable states from a variety of neural signals; and (iii) recent neural network approaches, informed by experimental results, to model the emergence of metastable dynamics. By discussing these topics, we aim to provide a cohesive view of how transitions between different states of activity may provide the neural underpinnings for essential functions such as perception, memory, expectation, or decision making, and more generally, how the study of metastable neural activity may advance our understanding of neural circuit function in health and disease.

Measuring particle size distribution and mass concentration of nanoplastics and microplastics: addressing some analytical challenges in the sub-micron size range.

HYPOTHESIS: The implementation of the proposal from the European Chemical Agency (ECHA) to restrict the use of nanoplastics (NP) and microplastics (MP) in consumer products will require reliable methods to perform size and mass-based concentration measurements. Analytical challenges arise at the nanometre to micrometre interface, e.g., 800 nm-10 µm, where techniques applicable at the nanometre scale reach their upper limit of applicability and approaches applicable at the micrometre scale must be pushed to their lower limits of detection. EXPERIMENTS: Herein, we compared the performances of nine analytical techniques by measuring the particle size distribution and mass-based concentration of polystyrene mixtures containing both nano and microparticles, with the educational aim to underline applicability and limitations of each technique. FINDINGS: Light scattering-based measurements do not have the resolution to distinguish multiple populations in polydisperse samples. Nanoparticle tracking analysis (NTA), nano-flowcytometry (nFCM) and asymmetric flow field flow fractionation hyphenated with multiangle light scattering (AF4-MALS) cannot measure particles in the micrometre range. Static light scattering (SLS) is not able to accurately detect particles below 200 nm, and similarly to transmission electron microscopy (TEM) and flow cytometry (FCM), is not suitable for accurate mass-based concentration measurements. Alternatives for high-resolution sizing and concentration measurements in the size range between 60 nm and 5 µm are tunable resistive pulse sensing (TRPS) and centrifugal liquid sedimentation (CLS), that can bridge the gap between the nanometre and micrometre range.

Expectation-induced modulation of metastable activity underlies faster coding of sensory stimuli.

Sensory stimuli can be recognized more rapidly when they are expected. This phenomenon depends on expectation affecting the cortical processing of sensory information. However, the mechanisms responsible for the effects of expectation on sensory circuits remain elusive. In the present study, we report a novel computational mechanism underlying the expectation-dependent acceleration of coding observed in the gustatory cortex of alert rats. We use a recurrent spiking network model with a clustered architecture capturing essential features of cortical activity, such as its intrinsically generated metastable dynamics. Relying on network theory and computer simulations, we propose that expectation exerts its function by modulating the intrinsically generated dynamics preceding taste delivery. Our model's predictions were confirmed in the experimental data, demonstrating how the modulation of ongoing activity can shape sensory coding. Altogether, these results provide a biologically plausible theory of expectation and ascribe an alternative functional role to intrinsically generated, metastable activity.

Atypical Post-Injection Reactions with Delayed Onset Following Glatiramer Acetate 40 mg: Need for Titration?

BACKGROUND: Glatiramer acetate (GA) 20 mg/day (GA20) is associated with immediate post-injection reactions (PIRs). For convenience of use, approved GA 40 mg three times weekly (GA40) delivers a similar weekly dose. The dose and concentration of a single GA40 injection are, however, twice as high as for GA20, and post-injection adverse events may differ. Cases of atypical PIRs to GA40 prompted us to systematically monitor such events. OBJECTIVE: The aim was to characterize atypical PIRs in multiple sclerosis (MS) patients treated with GA40. METHODS: Clinical practice data were prospectively collected in consecutive relapsing-remitting MS patients. Descriptive statistics for categorical and continuous variables, Mann-Whitney and Chi-squared tests for baseline comparisons, and Cox regression models for association of variables to first atypical PIRs were applied. RESULTS: Forty-six out of 173 patients (26.6%) given GA40 experienced any PIRs. Of those, 38 (22.0%) had atypical, 14 (8.1%) had combined typical and atypical, and 26 (15.0%) had recurrent atypical PIRs, most frequently shivering (13.3%) and nausea/vomiting (8.1%). Compared to typical PIRs, onset of atypical PIRs was significantly delayed (median 30 vs 1 min, p < 0.0001), and their median duration longer (median 120 vs 6 min, p = 0.00013). Previous exposure to GA20 was associated with a lower risk of atypical PIRs [hazard ratio (HR) = 0.35, 95% confidence interval (CI) 0.17-0.72, p = 0.0039]. Patients experiencing PIRs with GA20 were at elevated risk for atypical PIRs with GA40 (HR = 5.75, 95% CI 1.66-19.94, p = 0.0059). CONCLUSIONS: Atypical PIRs with GA40, especially gastrointestinal symptoms and/or fever/shivering, had a delayed onset and occurred in a significant proportion of our patients. Their real prevalence should be assessed in appropriately designed studies accounting for  nocebo responses. Initial dose titration might reduce PIR frequency.

Post-rotavirus vaccine intussusception in identical twins: A case report.

The intussusception is one of the most frequent causes of occlusive syndrome in infants and in children. (1) The mesenteric lymphadenopathy, wich is very rare post rotavirus vaccination, can cause intussusception, (2-5) especially in genetically predisposed individuals. (6) There is an association between intussusception and some classes of genotype. (7-9) Two infants aged 3 months, vaccinated against rotavirus. After about a week, one of the 2 identical infants presented inconsolable crying, vomiting, loose stools mixed with blood, and was diagnosed with bowel obstruction with intussusception. He was operated in urgency. After a few hours, his brother presented vomiting, and was admitted to our Hospital for suspected intussusception. The controls carried out have confirmed the presence of intussusception that was treated early, before the onset of severe symptoms. The incidence of post rotavirus vaccine intussusception is very low. The determining factor hypothetically might be linked to the presence of a genotype that exposes infants to a greater risk of developing mesenteric lymphadenitis and intussusception. In our case, the diagnosis of intussusception occurred in a twin, which allowed us to recognize early symptoms which accused the brother and schedule the surgery with less urgency. Our experience may want to sensitize families and pediatricians to report cases of intussusception given a theoretical familiar association. The study of the genotype could be decisive for or not to exclude the presence of a risk of invagination, thus avoiding vaccination.

Occurrence of thanatophoric dysplasia type I (R248C) and hypochondroplasia (N540K) mutations in two patients with achondroplasia phenotype.

We report two patients with clinical and radiological findings of achondroplasia, who had the most common FGFR3 mutation occurring in thanatophoric dysplasia type I and hypochondroplasia, respectively. Thanatophoric dysplasia is usually a lethal condition, but the patient carrying this mutation is alive and presents a medical history similar to that of patients with achondroplasia. The events leading to such a discrepancy between genotype and phenotype are unclear. These rare cases may influence an appropriate medical and genetic counseling.

Brachyphalangy, feet polydactyly, absent/hypoplastic tibiae: a further case and review of main diagnostic findings.

In 1997, Baraitser et al. (Clin Dysmorphol 6:111-121) described a patient with a complex phenotype characterized by facial dysmorphism, micropenis, brachydactyly, pre-axial polydactyly of the feet and tibial aplasia. We report here a patient with similar features.

Congenital hypertrichosis, cardiomegaly, and osteochondrodysplasia (Cantú syndrome): a new case with unusual radiological findings.

We report on a new case of a syndrome first described by Cantú et al. [1982: Hum Genet 60:36-41] comprising congenital hypertrichosis, "coarse" facial appearance, and mild osteochondrodysplasia. Our case has some unusual radiological findings, namely proximal and distal megaepiphyses of long bones and advanced bone age.

A Cys634Gly substitution of the RET proto-oncogene in a family with recurrence of multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis.

Germ-line mutations of the RET proto-oncogene, involving five cysteine residues at codons 609, 611, 618, 620 and 634, are associated with two variants of the inherited cancer syndrome multiple endocrine neoplasia type 2: type 2A and familial medullary thyroid carcinoma. The association of multiple endocrine neoplasia type 2A with the dermatological disorder cutaneous lichen amyloidosis has already been reported, and mutations in the Cys634 have been identified in different families. We describe here an additional pedigree in which multiple endocrine neoplasia type 2A and cutaneous lichen amyloidosis cosegregate. A Cys634Gly was identified by direct sequencing of the RET proto-oncogene exon 11 in the affected individuals. The mutation creates a new HaeIII site, and restriction analysis performed on all family members rules out the presence of the altered allele in two children and consequently the risk of developing thyroid tumors. These results emphasize the role of molecular analysis of the RET proto-oncogene in diagnosing presymptomatically those individuals at risk of inheriting the disease allele.

Unusual type of brachydactyly associated with intraventricular septal defect and deafness: a new condition?

We report a patient with brachydactyly associated with an intraventricular septal defect and sensorineural deafness. The second fingers had ulnar curvature. Radiographs showed bilateral hypoplastic middle phalanges of the 2nd and 5th fingers and the left 2nd digit showed hyperphalangy. The association of this unusual brachydactyly, intraventricular septal defect, and deafness does not conform to any known condition.

Phenotypic comparison of an osteogenesis imperfecta type IV proband with a de novo alpha2(I) Gly922 --> Ser substitution in type I collagen and an unrelated patient with an identical mutation.

We examined the type I collagen synthesized by cultured dermal fibroblasts from a patient affected with osteogenesis imperfecta (OI) type IV. Both normal and abnormal trimers were produced. The mutant collagen molecules were excessively modified intracellularly, had a melting temperature 4 degrees C lower than the control, were secreted at a reduced rate, and underwent delayed processing to mature alpha chains.Molecular investigations identified a G --> A transition in one COL1A2 allele, resulting in a Gly922 --> Ser substitution in the alpha2(I) chain. The proband's mutation was demonstrated to arise "de novo" by the absence of the mutant allele restriction enzyme pattern from parental genomic DNA.We analyzed the insoluble extracellular matrix deposited by long-term cultured fibroblasts from our patient and from a previously described unrelated individual who carries an identical substitution. In both cases, the mutant chain constituted 10-15% of the total alpha chains deposited.We also present here the first detailed comparison of phenotype between unrelated OI patients with an identical collagen mutation. These two patients are both Caucasian females, ages 8 and 9 years, each diagnosed as type IV OI by the Sillence classification. They have a similar phenotype including moderate skeletal fragility with several femur fractures, dentinogenesis imperfecta, wormian bone, and reduced height and weight. We conclude that this phenotype is related both to the location of this mutation and to the similar extent of matrix incorporation by the mutant chains. Molecular and biochemical studies of unrelated individuals with identical amino acid substitutions in type I collagen resulting in either similar or dissimilar clinical outcomes will make a significant contribution to identifying the factors involved in the modulation of the OI phenotype.

Hydrocephalus, skeletal anomalies, and mental disturbances in a mother and three daughters: a new syndrome.

We report on a family in which a mother and her 3 daughters have delayed psychomotor development and/or psychosis, hydrocephalus with white matter alterations, arachnoid cysts, skeletal anomalies consisting of brachydactyly, and Sprengel anomaly. Biochemical and cytogenetic analyses were normal on all 4 patients. The pattern of inheritance, clinical manifestations, and variability of expression suggest that this is a new hydrocephalus syndrome possibly transmitted as an X-linked dominant trait.

[Prenatal diagnosis of thanatophoric dysplasia at the 20th week of pregnancy using ultrasonography]. / Diagnosi prenatale di displasia tanatofora alla 20a settimana di gravidanza mediante ultrasonografia.

We report on prenatal diagnosis of a fetus with thanatophoric dysplasia type 1 at 20 weeks gestation. The ultrasonographic examination showed shortened bowed limbs, narrow chest, relatively large head, protuberant abdomen, and hydramnios. Radiological and histological studies confirmed the aborted fetus had thanatophoric dysplasia. The differential prenatal diagnosis with other skeletal dysplasia is discussed.

[Iniencephaly: description of a case]. / Iniencefalia: descrizione di un caso.

We report on a spontaneously aborted female fetus with iniencephaly. Iniencephaly is an uncommon, but not rare, abnormality which is characterized by defect of the squamous part of the occipital bone, and body and arch of the cervical vertebrae; by prolapse of the brain from distended occipital foramen; by severe lordosis with consequent uptilting face; and often by spina bifida. Iniencephaly may be associated with several other defects. The fetus reported here had no other defects.

F-syndrome (F-form of acro-pectoro-vertebral dysplasia): report on a second family.

We report on a father and daughter in the second known family affected with F-syndrome. The first family, with 8 affected members, was reported by Grosse et al. [1969: BD:OAS V (3):48-63]. F-syndrome, an autosomal-dominant trait, is mainly characterized by acral defects that may also involve the sternum and the lumbosacral spine. Synostoses between capitate and hamate, and between talus and navicular, are invariably present; other carpal and tarsal bones are sometimes incorporated into the fusion. The hand malformation is principally a malformation of the first 2 rays. In our patients, the short and malformed thumb was webbed with the index finger, which was radially deviated with duplication of the middle and distal phalanges. In the feet, polydactyly and severe metatarsal and toe anomalies were present. The father had a prominent sternum with pectus excavatum, whereas the daughter had no sternal deformity. Both of them had a mild failure of fusion of posterior arch L5 and/or S1.

Synpolydactyly (type II syndactyly) with aplasia/hypoplasia of the middle phalanges of the toes: report on a family with eight affected members in four generations.

We describe a new family with synpolydactyly (syndactyly type II) with 8 affected members in 4 generations. Aplasia/hypoplasia of the middle phalanges of the toes was also noted. In our opinion, this anomaly represents a frequent manifestation of synpolydactyly. No other major skeletal or extraskeletal malformations were present.

Peters'-Plus syndrome: report on an unusual case.

We report on a 10 1/2-years-old patient with clinical manifestations of Peters'-Plus syndrome. The patient had Peters' anomaly, slightly arched eyebrows, long eyelashes, a broad nasal tip; malformed and prominent ears, cleft lip and palate, brachydactyly, fingertip pads, severe growth deficiency, and mild mental retardation. Peters' anomaly is a defect of the anterior chamber of the eye, including central corneal opacity, thinning of the posterior aspect of the cornea and iridolenticulocorneal adhesions. Peters'-Plus syndrome is a disorder in which patients with Peters' anomaly are also found to have short stature, brachymedia, abnormal ears, cleft lip and palate, and mental retardation. Our patient showed Peters'-Plus syndrome associated with some clinical manifestations of the Kabuki make-up syndrome.

[Isolated macrodactyly or extremely circumscribed Proteus syndrome?]. / Macrodattilia isolata o Sindrome di Proteus estremamente circoscritta?

We report on two unrelated female patients with unilateral macrodactyly of the 1st and 2nd toes and of the 3rd, 4th, and 5th toes, respectively. In addition, they had a local plantar soft tissue lump and radiographically abnormally broad phalanges of the affected toes. These clinical manifestations may represent either an isolated macrodactyly or an extremely localized form of Proteus syndrome.