Poorer white matter microstructure predicts slower and more variable reaction time performance: evidence for the neural noise hypothesis in a large lifespan cohort

Most prior research in the neural and behavioral sciences has been focused on characterizing averages in cognition, brain characteristics, or behavior, and attempting to predict differences in these averages among individuals. However, this overwhelming focus on mean levels may leave us with an incomplete picture of what drives individual differences in behavioral phenotypes by ignoring the variability of behavior around an individual’s mean. In particular, better white matter (WM) structural microstructure has been hypothesized to support consistent behavioral performance by decreasing gaussian noise in signal transfer. In contrast, lower indices of white matter microstructure have been associated with greater within-subject variance in the ability to deploy performance-related resources, especially in clinical samples. We tested this ‘neural noise’ hypothesis in a large adult lifespan cohort (Cam-CAN) with over 2500 individuals in a (2681 behavioral sessions with 708 scans in adults aged 18–102) using measures of WM tract microstructure to predict mean levels and variability in reaction time performance on a simple behavioral task using a dynamic structural equation model (DSEM). We found broad support for neural noise hypothesis, such that lower WM microstructure predicted individual differences in separable components of behavioral performance estimated using DSEM, including slower mean responses and increased variability. These effects were robust when including age in the model, suggesting consistent effects of WM microstructure across the adult lifespan above and beyond concurrent effects of ageing. Crucially, these results demonstrate the utility of DSEM for modeling and predicting behavioral variability directly, and the promise of studying variability for understanding cognitive processes.

Intracranial electrophysiological recordings from the human brain during memory tasks with pupillometry

Data comprise intracranial EEG (iEEG) brain activity represented by stereo EEG (sEEG) signals, recorded from over 100 electrode channels implanted in any one patient across various brain regions. The iEEG signals were recorded in epilepsy patients (N = 10) undergoing invasive monitoring and localization of seizures when they were performing a battery of four memory tasks lasting approx. 1 hour in total. Gaze tracking on the task computer screen with estimating the pupil size was also recorded together with behavioral performance. Each dataset comes from one patient with anatomical localization of each electrode contact. Metadata contains labels for the recording channels with behavioral events marked from all tasks, including timing of correct and incorrect vocalization of the remembered stimuli. The iEEG and the pupillometric signals are saved in BIDS data structure to facilitate efficient data sharing and analysis.

A connectivity-constrained computational account of topographic organization in primate high-level visual cortex

Inferotemporal (IT) cortex in humans and other primates is topographically organized, containing multiple hierarchically organized areas selective for particular domains, such as faces and scenes. This organization is commonly viewed in terms of evolved domain-specific visual mechanisms. Here, we develop an alternative, domain-general and developmental account of IT cortical organization. The account is instantiated in interactive topographic networks (ITNs), a class of computational models in which a hierarchy of model IT areas, subject to biologically plausible connectivity-based constraints, learns high-level visual representations optimized for multiple domains. We find that minimizing a wiring cost on spatially organized feedforward and lateral connections, alongside realistic constraints on the sign of neuronal connectivity within model IT, results in a hierarchical, topographic organization. This organization replicates a number of key properties of primate IT cortex, including the presence of domain-selective spatial clusters preferentially involved in the representation of faces, objects, and scenes; columnar responses across separate excitatory and inhibitory units; and generic spatial organization whereby the response correlation of pairs of units falls off with their distance. We thus argue that topographic domain selectivity is an emergent property of a visual system optimized to maximize behavioral performance under generic connectivity-based constraints.

Up-And-Down γ-Synuclein Transcription in Dopamine Neurons Translates Into Changes in Dopamine Neurotransmission and Behavioral Performance in Mice

The synuclein family consists of α-, β-, and γ-Synuclein (α-Syn, β-Syn, and γ-Syn), expressed in the neurons and concentrated in synaptic terminals. While α-Syn is at the center of interest due to its implication in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, limited information exists on the other members. The current study aimed at investigating the biological role of γ-Syn controlling the midbrain dopamine (DA) function. We generated two different mouse models with i) γ-Syn overexpression induced by an adeno-associated viral vector and ii) γ-Syn knockdown induced by a ligand-conjugated antisense oligonucleotide, to modify the endogenous γ-Syn transcription levels in midbrain DA neurons. The progressive overexpression of γ-Syn decreased DA neurotransmission in the nigrostriatal and mesocortical pathways. In parallel, mice evoked motor deficits in the rotarod and impaired cognitive performance as assessed by novel object recognition, passive avoidance, and Morris water maze tests. Conversely, acute γ-Syn knockdown selectively in DA neurons facilitated forebrain DA neurotransmission. Importantly, modifications in γ-Syn expression did not induce the loss of DA neurons or changes in α-Syn expression. Collectively, our data strongly suggest that DA re-lease/re-uptake processes in the nigrostriatal and mesocortical pathways are partially dependent on SNc/VTA γ-Syn transcription levels, and are linked to modulation of DA transporter function, similar to α-Syn.

Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia

In agreement with the neurodevelopmental hypothesis of schizophrenia, prenatal exposure of Sprague-Dawley rats to the antimitotic agent methylazoxymethanol acetate (MAM) at gestational day 17 produces long-lasting behavioral alterations such as social withdrawal and cognitive impairment in adulthood, mimicking a schizophrenia-like phenotype. These abnormalities were preceded at neonatal age both by the delayed appearance of neonatal reflexes, an index of impaired brain maturation, and by higher 2-arachidonoylglycerol (2-AG) brain levels. Schizophrenia-like deficits were reversed by early treatment [from postnatal day (PND) 2 to PND 8] with the CB1 antagonist/inverse agonist AM251 (0.5 mg/kg/day). By contrast, early CB1 blockade affected the behavioral performance of control rats which was paralleled by enhanced 2-AG content in the prefrontal cortex (PFC). These results suggest that prenatal MAM insult leads to premorbid anomalies at neonatal age via altered tone of the endocannabinoid system, which may be considered as an early marker preceding the development of schizophrenia-like alterations in adulthood.

Effects of the DRD4 −521 C/T SNP on Local Neural Activity and Functional Connectivity in Children With ADHD

Objective: The present study aimed to investigate the effects of the dopamine receptor D4 (DRD4) −521 C/T single-nucleotide polymorphism on brain function among children with attention deficit hyperactivity disorder (ADHD) and to evaluate whether brain function is associated with behavioral performance among this demographic.Methods: Using regional homogeneity, fractional amplitude low-frequency fluctuation, and functional connectivity as measurement indices, we compared differences in resting-state brain function between 34 boys with ADHD in the TT homozygous group and 37 boys with ADHD in the C-allele carrier group. The Conners' Parent Rating Scale, the SNAP-IV Rating Scale, the Stroop Color Word Test, the go/no-go task, the n-back task, and the working memory index within the Wechsler Intelligence Scale for Children-Fourth Edition were selected as comparative indicators in order to test effects on behavioral performance.Results: We found that TT homozygotes had low behavioral performance as compared with C-allele carriers. The regional homogeneity for TT homozygotes decreased in the right middle occipital gyrus and increased in the right superior frontal gyrus as compared with C-allele carriers. In addition, the right middle occipital gyrus and the right superior frontal gyrus were used as the seeds of functional connectivity, and we found that the functional connectivity between the right middle occipital gyrus and the right cerebellum decreased, as did the functional connectivity between the right superior frontal gyrus and the angular gyrus. No statistically significant differences were observed in the respective brain regions when comparing the fractional amplitudes for low-frequency fluctuation between the two groups. Correlation analyses demonstrated that the fractional amplitude low-frequency fluctuation in the precentral gyrus for TT homozygotes were statistically significantly correlated with working memory.Conclusions: We found differing effects of DRD4 −521 C/T polymorphisms on brain function among boys with ADHD. These findings promote our understanding of the genetic basis for neurobiological differences observed among children with ADHD, but they must be confirmed in larger samples.

Electrobehavioral phenotype and seizure pharmacosensitivity in a novel mouse model of patient-derived SLC6A1 S295L mutation-associated neurodevelopmental epilepsy

Solute carrier family 6 member 1 (SLC6A1) gene encodes GAT-1, a GABA transporter expressed on glia and presynaptic terminals of inhibitory neurons. Mutations in SLC6A1 are associated with myoclonic atonic epilepsy, absence epilepsy, autism, and intellectual disability. However, the mechanisms leading to these defects are unknown. Here, we used a novel mouse model harboring a point mutation (S295L) recently identified in the human SLC6A1 gene that results in impaired membrane trafficking of the GAT-1 protein. We performed chronic wireless telemetry recordings of heterozygous (GAT-1S295L/+) mice, and of mice lacking one or both copies of the Slc6a1 gene (GAT-1+/- and GAT-1-/-). We assessed their behaviors and pharmacosensitivity, and investigated the relationship between seizure burden and behavioral performance. GAT-1S295L/+ mice exhibited frequent spike-wave discharges (SWDs) associated with behavioral arrest, and there was a dose-effect relationship between GAT-1 gene copy number and the severity of electrocorticogram (ECoG) abnormalities. Seizure burden was inversely correlated with behavioral performance. Forelimb grip strength was reduced in female mice. Acute administration of GAT-1 antagonist NO-711 induced SWDs in wild-type mice, exacerbated the phenotype in GAT-1S295L/+ and GAT-1+/- mice, and had no effect on GAT-1-/- mice lacking the drug target. By contrast, ethosuximide normalized the ECoG in GAT-1S295L/+ and GAT-1+/- mice. In conclusion, GAT-1S295L/+ mice show haploinsufficiency with evidence of GAT-1 hypofunction. This mouse model reconstitutes major aspects of human disease and thus provides a useful preclinical model for drug screening and gene therapy.

Belief in Control: Voluntary Choice Enhances Subsequent Task Performance under Undefeated Choice-Outcome Causation

Humans are believed to have volition through which they act upon and change the external environment. As an exercise of volition, making a voluntary choice facilitates the subsequent behavioral performance relative to a forced choice. However, it is unclear how this facilitation is constrained by the perceived relationship between a choice and its outcome. In a series of experiments, participants were free or forced to choose one of two presented pictures. The outcome of the choice was then revealed, which could be always the chosen picture or always the unchosen picture (i.e., a confirmed choice-outcome causation), a blank screen with no picture at all (i.e., an unrevealed choice-outcome relation), the chosen or unchosen picture with equal probability (i.e., a defeated choice-outcome causation), or a third picture different from the two preceding options (again, a defeated choice-outcome causation). Participants then complete a visual search task with the task-irrelevant picture (or the blank screen) serving as a background. Results showed that the search performance was improved after a voluntary choice under both the confirmed causation and the unrevealed relation, but not under the defeated causation. Over individuals, the improved performance due to voluntary choice under confirmed causation positively correlated with the improved performance under the unrevealed relation, and with the reported belief in controlling the outcome of the choice. Our findings suggest that the exercise of volition motivates subsequent behavior, and this motivation is restricted to an “undefeated” choice-outcome causation which affords a belief in controlling the outcome by exerting volition.

Meter without rhythmic pattern repetitions increases pre-attentive processing

Processing musical meter – the organization of time into regular cycles of strong and weak beats – requires abstraction from the varying rhythmic surface. Several studies investigated whether meter processing requires attention, or if it can be both pre-attentive and attentive. While findings on temporal expectation (processing meter per se) indicated benefits of attention, studies on meter processing in a more complex, dual-task context (meter used for temporal orientation) consistently reported pre-attentive processing. Also, while surface-based approaches to meter (meter aided by pattern repetition) showed some benefits of attention, structural approaches (meter not aided by pattern repetition, increased complexity) found pre-attentive-only processing. Therefore, in the present study we hypothesized that pre-attentive processing increases with cognitive load, and we compared surface with structural meter processing. Supporting our hypothesis, we saw improved behavioral performance for surface meter, as well as EEG evidence that structural meter elicits pre-attentive processing (pre-attentive P1) while surface meter does not (attentive-only P1). Our findings highlight the need for increased awareness in approaches to meter processing and support the idea that increased cognitive demand may recruit pre-attentive processing of temporal structure.