Correlation of growth differentiation factor-5 + 104T>C polymorphism with the risk of knee, hand, and hip osteoarthritis: a case-control study and meta-analysis based on 47 case-control studies.

Osteoarthritis (OA) arises from a intricate interplay of genetic and environmental factors. Numerous studies have explored the link between the growth differentiation factor 5 (GDF-5) +104T>C polymorphism and OA risk, but the findings have been inconclusive. We carried out a case-control study with 704 OA cases and 418 healthy controls. Furthermore, we conducted a meta-analysis by thoroughly searching the literature for relevant studies published until 1 September, 2023. The combined odds ratio and 95% confidence intervals were used to assess the correlation's strength. A total of 47 independent case-control studies, including 17,602 OA cases and 30,947 controls, were analyzed. Of these, 31 studies (11,176 cases, 16,724 controls) focused on knee OA, 8 studies (3,973 cases, 8,055 controls) examined hip OA, and 6 studies (2244 cases, 5965 controls) investigated hand OA. Overall, our findings suggest that the GDF-5 + 104T>C polymorphism has a protectibe role in development of OA in global scale. Subgroup analyses by ethnicity indicated that this genetic variation provides protection against OA in Caucasian, Asian, and African populations. Further subgroup analysis based on the type of OA showed a decreased risk of knee and hand OA associated with this variation, but not for hip OA. Our combined data indicates that the GDF-5 + 104T>C polymorphism offers protection against the development of OA in general, as well as knee and hand OA. Nevertheless, there was no correlation found between this polymorphism and the development of hip OA.

Spontaneous α Brain Dynamics Track the Episodic "When".

Across species, neurons track time over the course of seconds to minutes, which may feed the sense of time passing. Here, we asked whether neural signatures of time-tracking could be found in humans. Participants stayed quietly awake for a few minutes while being recorded with magnetoencephalography (MEG). They were unaware they would be asked how long the recording lasted (retrospective time) or instructed beforehand to estimate how long it will last (prospective timing). At rest, rhythmic brain activity is nonstationary and displays bursts of activity in the alpha range (α: 7-14 Hz). When participants were not instructed to attend to time, the relative duration of α bursts linearly predicted individuals' retrospective estimates of how long their quiet wakefulness lasted. The relative duration of α bursts was a better predictor than α power or burst amplitude. No other rhythmic or arrhythmic activity predicted retrospective duration. However, when participants timed prospectively, the relative duration of α bursts failed to predict their duration estimates. Consistent with this, the amount of α bursts was discriminant between prospective and retrospective timing. Last, with a control experiment, we demonstrate that the relation between α bursts and retrospective time is preserved even when participants are engaged in a visual counting task. Thus, at the time scale of minutes, we report that the relative time of spontaneous α burstiness predicts conscious retrospective time. We conclude that in the absence of overt attention to time, α bursts embody discrete states of awareness constitutive of episodic timing.SIGNIFICANCE STATEMENT The feeling that time passes is a core component of consciousness and episodic memory. A century ago, brain rhythms called "α" were hypothesized to embody an internal clock. However, rhythmic brain activity is nonstationary and displays on-and-off oscillatory bursts, which would serve irregular ticks to the hypothetical clock. Here, we discovered that in a given lapse of time, the relative bursting time of α rhythms is a good indicator of how much time an individual will report to have elapsed. Remarkably, this relation only holds true when the individual does not attend to time and vanishes when attending to it. Our observations suggest that at the scale of minutes, α brain activity tracks episodic time.

Characterizing endogenous delta oscillations in human MEG.

Rhythmic activity in the delta frequency range (0.5-3 Hz) is a prominent feature of brain dynamics. Here, we examined whether spontaneous delta oscillations, as found in invasive recordings in awake animals, can be observed in non-invasive recordings performed in humans with magnetoencephalography (MEG). In humans, delta activity is commonly reported when processing rhythmic sensory inputs, with direct relationships to behaviour. However, rhythmic brain dynamics observed during rhythmic sensory stimulation cannot be interpreted as an endogenous oscillation. To test for endogenous delta oscillations we analysed human MEG data during rest. For comparison, we additionally analysed two conditions in which participants engaged in spontaneous finger tapping and silent counting, arguing that internally rhythmic behaviours could incite an otherwise silent neural oscillator. A novel set of analysis steps allowed us to show narrow spectral peaks in the delta frequency range in rest, and during overt and covert rhythmic activity. Additional analyses in the time domain revealed that only the resting state condition warranted an interpretation of these peaks as endogenously periodic neural dynamics. In sum, this work shows that using advanced signal processing techniques, it is possible to observe endogenous delta oscillations in non-invasive recordings of human brain dynamics.

Telomere length and early trauma in schizophrenia.

BACKGROUND: Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects. METHODS: The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR. OUTCOMES: Cases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91±0.74 and 1.83±0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher's R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males' cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma. INTERPRETATION: This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field.

Prestimulus Alpha Oscillations and the Temporal Sequencing of Audiovisual Events.

Perceiving the temporal order of sensory events typically depends on participants' attentional state, thus likely on the endogenous fluctuations of brain activity. Using magnetoencephalography, we sought to determine whether spontaneous brain oscillations could disambiguate the perceived order of auditory and visual events presented in close temporal proximity, that is, at the individual's perceptual order threshold (Point of Subjective Simultaneity [PSS]). Two neural responses were found to index an individual's temporal order perception when contrasting brain activity as a function of perceived order (i.e., perceiving the sound first vs. perceiving the visual event first) given the same physical audiovisual sequence. First, average differences in prestimulus auditory alpha power indicated perceiving the correct ordering of audiovisual events irrespective of which sensory modality came first: a relatively low alpha power indicated perceiving auditory or visual first as a function of the actual sequence order. Additionally, the relative changes in the amplitude of the auditory (but not visual) evoked responses were correlated with participant's correct performance. Crucially, the sign of the magnitude difference in prestimulus alpha power and evoked responses between perceived audiovisual orders correlated with an individual's PSS. Taken together, our results suggest that spontaneous oscillatory activity cannot disambiguate subjective temporal order without prior knowledge of the individual's bias toward perceiving one or the other sensory modality first. Altogether, our results suggest that, under high perceptual uncertainty, the magnitude of prestimulus alpha (de)synchronization indicates the amount of compensation needed to overcome an individual's prior in the serial ordering and temporal sequencing of information.

High-frequency neural activity predicts word parsing in ambiguous speech streams.

During speech listening, the brain parses a continuous acoustic stream of information into computational units (e.g., syllables or words) necessary for speech comprehension. Recent neuroscientific hypotheses have proposed that neural oscillations contribute to speech parsing, but whether they do so on the basis of acoustic cues (bottom-up acoustic parsing) or as a function of available linguistic representations (top-down linguistic parsing) is unknown. In this magnetoencephalography study, we contrasted acoustic and linguistic parsing using bistable speech sequences. While listening to the speech sequences, participants were asked to maintain one of the two possible speech percepts through volitional control. We predicted that the tracking of speech dynamics by neural oscillations would not only follow the acoustic properties but also shift in time according to the participant's conscious speech percept. Our results show that the latency of high-frequency activity (specifically, beta and gamma bands) varied as a function of the perceptual report. In contrast, the phase of low-frequency oscillations was not strongly affected by top-down control. Whereas changes in low-frequency neural oscillations were compatible with the encoding of prelexical segmentation cues, high-frequency activity specifically informed on an individual's conscious speech percept.

Olfactory performance segregates effects of anhedonia and anxiety on social function in patients with schizophrenia.

BACKGROUND: Social dysfunction is common among individuals with schizophrenia. While often attributed to anhedonia, social dysfunction could also result from unrecognized anxiety. We examined the contributions of anhedonia and anxiety to social function using olfactory function to examine whether the domains had separate underpinnings. METHODS: We assessed anhedonia, anxiety and social function as well as olfactory function in well-characterized patients with schizophrenia or schizoaffective disorder and healthy controls. RESULTS: We included 56 patients and 37 controls in our study. Patients exhibited significantly higher levels of anhedonia and anxiety than controls, and the domains were highly correlated in patients. The combination of anhedonia and anxiety more strongly predicted social dysfunction than either measure alone. Smell identification was differentially related to the symptoms, with better performance predicting less anhedonia but more social fear in male patients. LIMITATIONS: The use of self-report measures precludes differentiation between recollected or recounted experience. Aside from smell identification and odour threshold, additional measures of olfaction may be considered for future studies. CONCLUSION: Anhedonia and anxiety were strongly correlated and both negatively impacted social function. The olfactory biomarker results support the conclusion that these domains are separate. Social function in patients with schizophrenia may improve with interventions for anxiety, even in the presence of marked negative symptoms.

Disruption of hierarchical predictive coding during sleep.

When presented with an auditory sequence, the brain acts as a predictive-coding device that extracts regularities in the transition probabilities between sounds and detects unexpected deviations from these regularities. Does such prediction require conscious vigilance, or does it continue to unfold automatically in the sleeping brain? The mismatch negativity and P300 components of the auditory event-related potential, reflecting two steps of auditory novelty detection, have been inconsistently observed in the various sleep stages. To clarify whether these steps remain during sleep, we recorded simultaneous electroencephalographic and magnetoencephalographic signals during wakefulness and during sleep in normal subjects listening to a hierarchical auditory paradigm including short-term (local) and long-term (global) regularities. The global response, reflected in the P300, vanished during sleep, in line with the hypothesis that it is a correlate of high-level conscious error detection. The local mismatch response remained across all sleep stages (N1, N2, and REM sleep), but with an incomplete structure; compared with wakefulness, a specific peak reflecting prediction error vanished during sleep. Those results indicate that sleep leaves initial auditory processing and passive sensory response adaptation intact, but specifically disrupts both short-term and long-term auditory predictive coding.

Inhibition and structural changes of liver alkaline phosphatase by tramadol.

Tramadol is a potent analgesic drug which interacts with mu-opioid and has low effect on other opioid receptors. Unlike other opioids, it has no clinically significant effect on respiratory or cardiovascular parameters. Alakaline phosphatase is a hydrolase enzyme that prefers alkaline condition and removes phosphate group from different substrates. In this study, the interaction between tramadol and calf liver alkaline phosphatase was investigated. The results showed that tramadol can bind to alakaline phosphatase and inhibit the enzyme in an un-competitive manner. Ki and IC50 values of tramadol were determined as about 91 and 92 µM, respectively. After enzyme purification, structural changes on alakaline phosphatase-drug interaction were studied by circular dichroism and fluorescence measurement. These data revealed the alteration in the content of secondary structures and also conformational changes in enzyme occurred when the drug bound to enzyme-substrate complex.

Supramodal processing optimizes visual perceptual learning and plasticity.

Multisensory interactions are ubiquitous in cortex and it has been suggested that sensory cortices may be supramodal i.e. capable of functional selectivity irrespective of the sensory modality of inputs (Pascual-Leone and Hamilton, 2001; Renier et al., 2013; Ricciardi and Pietrini, 2011; Voss and Zatorre, 2012). Here, we asked whether learning to discriminate visual coherence could benefit from supramodal processing. To this end, three groups of participants were briefly trained to discriminate which of a red or green intermixed population of random-dot-kinematograms (RDKs) was most coherent in a visual display while being recorded with magnetoencephalography (MEG). During training, participants heard no sound (V), congruent acoustic textures (AV) or auditory noise (AVn); importantly, congruent acoustic textures shared the temporal statistics - i.e. coherence - of visual RDKs. After training, the AV group significantly outperformed participants trained in V and AVn although they were not aware of their progress. In pre- and post-training blocks, all participants were tested without sound and with the same set of RDKs. When contrasting MEG data collected in these experimental blocks, selective differences were observed in the dynamic pattern and the cortical loci responsive to visual RDKs. First and common to all three groups, vlPFC showed selectivity to the learned coherence levels whereas selectivity in visual motion area hMT+ was only seen for the AV group. Second and solely for the AV group, activity in multisensory cortices (mSTS, pSTS) correlated with post-training performances; additionally, the latencies of these effects suggested feedback from vlPFC to hMT+ possibly mediated by temporal cortices in AV and AVn groups. Altogether, we interpret our results in the context of the Reverse Hierarchy Theory of learning (Ahissar and Hochstein, 2004) in which supramodal processing optimizes visual perceptual learning by capitalizing on sensory-invariant representations - here, global coherence levels across sensory modalities.

Intellectual developmental disorders: towards a new name, definition and framework for "mental retardation/intellectual disability" in ICD-11.

Although "intellectual disability" has widely replaced the term "mental retardation", the debate as to whether this entity should be conceptualized as a health condition or as a disability has intensified as the revision of the World Health Organization (WHO)'s International Classification of Diseases (ICD) advances. Defining intellectual disability as a health condition is central to retaining it in ICD, with significant implications for health policy and access to health services. This paper presents the consensus reached to date by the WHO ICD Working Group on the Classification of Intellectual Disabilities. Literature reviews were conducted and a mixed qualitative approach was followed in a series of meetings to produce consensus-based recommendations combining prior expert knowledge and available evidence. The Working Group proposes replacing mental retardation with intellectual developmental disorders, defined as "a group of developmental conditions characterized by significant impairment of cognitive functions, which are associated with limitations of learning, adaptive behaviour and skills". The Working Group further advises that intellectual developmental disorders be incorporated in the larger grouping (parent category) of neurodevelopmental disorders, that current subcategories based on clinical severity (i.e., mild, moderate, severe, profound) be continued, and that problem behaviours be removed from the core classification structure of intellectual developmental disorders and instead described as associated features.

Time-resolved diffusing wave spectroscopy with a CCD camera.

We show how time-resolved measurements of the diffuse light transmitted through a thick scattering slab can be performed with a standard CCD camera, thanks to an interferometric protocol. Time-resolved correlations measured at a fixed photon transit time are also presented. The high number of pixels of the camera allows us to attain a quite good sensitivity for a reasonably low acquisition time.

Ultimate spatial resolution with Diffuse Optical Tomography.

We evaluate the ultimate transverse spatial resolution that can be expected in Diffuse Optical Tomography, in the configuration of projection imaging. We show how such a performance can be approached using time-resolved measurements and reasonable assumptions, in the context of a linearized diffusion model.

Microcephalin, a gene regulating brain size, continues to evolve adaptively in humans.

The gene Microcephalin (MCPH1) regulates brain size and has evolved under strong positive selection in the human evolutionary lineage. We show that one genetic variant of Microcephalin in modern humans, which arose approximately 37,000 years ago, increased in frequency too rapidly to be compatible with neutral drift. This indicates that it has spread under strong positive selection, although the exact nature of the selection is unknown. The finding that an important brain gene has continued to evolve adaptively in anatomically modern humans suggests the ongoing evolutionary plasticity of the human brain. It also makes Microcephalin an attractive candidate locus for studying the genetics of human variation in brain-related phenotypes.