Biology subjects

Garic, D.

Publications and source records attributed to Garic, D..

9 recordsLinked to original sources

bioRxiv2026

LRRC57/RABIN is a presynaptic inhibitor of Rab GTPases in glutamatergic neurons

Synaptic vesicle cycling, if not properly constrained, can result in excessive neurotransmitter release and subsequent neural pathology. Rab GTPases orchestrate synaptic vesicle trafficking through GTP-dependent interactions with effector proteins, but the restraining mechanism of these interactions is unknown. Here we identify LRRC57 (or RABIN for RAB INhibitor), a conserved brain-enriched protein in glutamatergic synapses that binds multiple GTP-loaded synaptic Rabs and competitively blocks access to their effectors. Loss of Rabin increased glutamate release, expanded vesicle pools, accelerated vesicle turnover, and produced circuit hyperexcitability with epileptiform activity, which was mitigated by an antiepileptic agent that targets presynaptic function. Conversely, overexpression of the Rabin gene suppressed neurotransmitter release and protected against induced seizures and persistent epileptiform discharges. Together, these findings define a noncanonical decoy-effector mechanism that constrains presynaptic Rab signaling to preserve excitatory circuit stability.

neuroscience↗

bioRxiv2026

Variation in infant subcortical brain development from 6 to 12 months in Down syndrome

IntroductionDown syndrome (DS), arising from Trisomy 21, is the most common genetic condition associated with intellectual disability. While smaller total brain volumes have been consistently observed in DS, no longitudinal neuroimaging studies have examined volumetric brain development in DS during infancy, a period of rapid neural growth when interventions may have the greatest impact. MethodHigh-resolution T1- and T2-weighted images were acquired during natural sleep in a multisite longitudinal cohort of 44 infants with DS and 39 control infants without DS at ages 6 and 12 months. Neuroimaging data were harmonized to reduce batch effects, and a novel deep-learning, repeated-measures segmentation approach was applied to optimize neuroanatomical segmentations. Total intracranial volume (ICV) and bilateral absolute subcortical volumes (amygdala, caudate, hippocampus, pallidum, putamen, thalamus) were first directly compared in infants with and without DS at 6 and 12 months. Hierarchical linear modeling (HLM) evaluated longitudinal group differences for each structure, accounting for sex, gestational age, and laterality. Subcortical group differences estimated by HLM were also compared to group differences in total ICV. ResultsICV in infants with DS was lower than controls at 6 months (12.6%; p<.001) and 12 months (16.3%; p<.001). Subcortical structures displayed a range of lower volumes (6.9%-13.1%; ps[≤].003) in infants with DS, although the caudate and putamen were exceptions. Caudate volumes were on average lower in DS but not significantly different from controls, while putamen volumes were on average higher in DS but not significantly different from controls, except for the right putamen, which was significantly larger (5.3%; p=.018) at 6 months. In HLM, ICV and all subcortical structures showed slower growth in DS from 6 to 12 months, except for the amygdala and putamen, which displayed similar growth rates to controls. DS-associated reductions in subcortical volumes were similar in magnitude to ICV, although 12-month caudate and 6- and 12-month putamen volumes were enlarged relative to ICV. ConclusionInfants with DS exhibited substantially reduced ICV and widespread reductions in subcortical volumes and growth from 6-12 months. Across a range of volumetric differences, findings were most distinct in the basal ganglia, for which volume reductions were attenuated in the caudate, while the putamen was uniquely enlarged with comparable growth to controls. These observations support early regional specificity in the neural impact of Trisomy 21 and underscore the utility of infant neuroimaging to inform biologically based interventions and clinical trial readiness in DS.

neuroscience↗

bioRxiv2025

Brain Microstructure and Obesity Risk in Early Childhood: Insights from Restriction Spectrum Imaging

Pediatric obesity is a growing public health concern, yet little is known about the neurobiological underpinnings of obesity risk in early childhood. Using restriction spectrum imaging (RSI), we examined associations between adiposity and brain microstructure in a cross-sectional sample of 159 children aged 4-7 years, including 81 with ADHD and 78 typically developing (TD) peers. We focused on RSI-derived measures of restricted diffusion--specifically restricted normalized isotropic (RNI), directional (RND), and total (RNT) signals--as indicators of cellular density in subcortical and cortical regions implicated in reward and salience processing. Body mass index (BMI), percent body fat, waist circumference, and obesity status were assessed. Higher BMI, but not other adiposity measures, was significantly associated with increased RNI in the right insula, nucleus accumbens (NAcc), and putamen, as well as increased RNT in the right insula and pallidum. These findings suggest early microstructural alterations in reward-related circuits, consistent with theories of diet-related neuroinflammation. Contrary to hypotheses, ADHD diagnosis did not moderate the associations, and anthropometric profiles were similar between groups. This suggests a shared neural pathway linking early adiposity and brain structure, independent of diagnostic status. Our findings replicate and extend prior work in older children, highlighting BMI as the most sensitive marker of obesity-related brain differences in early childhood. These results underscore the potential of RSI as a tool for identifying early neural risk markers of obesity and inform future efforts to design preventive interventions during critical developmental windows.

neuroscience↗

bioRxiv2024

Structural Development of Speech Networks in Young Children at Risk for Speech Disorder

Characterizing the structural development of the neural speech network in early childhood is important to understand speech acquisition. To investigate speech in the developing brain, 94 children aged 4-7-years-old were scanned using diffusion weighted imaging (DWI) magnetic resonance imaging (MRI). In order to increase sample size and performance variability, we included children who were diagnosed with attention-deficit hyperactivity disorder (ADHD) from a larger ongoing study. Additionally, each child completed the Syllable Repetition Task (SRT), a validated measure of phoneme articulation. The DWI data were modeled using restriction spectrum imaging (RSI) to measure restricted and hindered diffusion properties in both grey and white matter. Consequently, we analyzed the diffusion data using both whole brain analysis, and automated fiber quantification (AFQ) analysis to establish tract profiles for each of six fiber pathways thought to be important for supporting speech development. In the whole brain analysis, we found that SRT performance was associated with restricted diffusion in bilateral inferior frontal gyrus, pars opercularis, right pre-supplementary and supplementary motor area, and bilateral cerebellar grey matter (p < .005). Age moderated these associations in left pars opercularis and frontal aslant tract (FAT). However, in both cases only the cerebellar findings survived a cluster correction. We also found associations between SRT performance and restricted diffusion in cortical association fiber pathways, especially left FAT, and in the cerebellar peduncles. Analyses using automated fiber quantification (AFQ) highlighted differences in high and low performing children along specific tract profiles, most notably in left but not right FAT, in bilateral SLFIII, and in the cerebellar peduncles. These findings suggest that individual differences in speech performance are reflected in structural grey and white matter differences as measured by restricted and hindered diffusion metrics, and offer important insights into developing brain networks supporting speech in very young children.

neuroscience↗

bioRxiv2024

Reduced recruitment of inhibitory control regions in very young children with ADHD during a modified Kiddie Continuous Performance Task: a fMRI study.

Attention-Deficit/Hyperactivity Disorder (ADHD) symptom profiles are known to undergo changes throughout development, rendering the neurobiological assessment of ADHD challenging across different developmental stages. Particularly in young children (ages 4 to 7 years), measuring inhibitory control network activity in the brain has been a formidable task due to the lack of child-friendly functional Magnetic Resonance Imaging (fMRI) paradigms. This study aims to address these difficulties by focusing on measuring inhibitory control in very young children within the MRI environment. A total of 56 children diagnosed with ADHD and 78 typically developing (TD) 4-7-year-old children were examined using a modified version of the Kiddie-Continuous Performance Test (K-CPT) during BOLD fMRI to assess inhibitory control. We concurrently evaluated their performance on the established and standardized K-CPT outside the MRI scanner. Our findings suggest that the modified K-CPT effectively elicited robust and expected brain activity related to inhibitory control in both groups. Comparisons between the two groups revealed subtle differences in brain activity, primarily observed in regions associated with inhibitory control, such as the inferior frontal gyrus, anterior insula, dorsal striatum, medial pre-supplementary motor area (pre-SMA), and cingulate cortex. Notably, increased activity in the right anterior insula was associated with improved response time (RT) and reduced RT variability on the K-CPT administered outside the MRI environment, although this did not survive statistical correction for multiple comparisons. In conclusion, our study successfully overcame the challenges of measuring inhibitory control in very young children within the MRI environment by utilizing a modified K-CPT during BOLD fMRI. These findings shed light on the neurobiological correlates of inhibitory control in ADHD and TD children, provide valuable insights for understanding ADHD across development, and potentially inform ADHD diagnosis and intervention strategies. The research also highlights remaining challenges with task fMRI in very young clinical samples.

neuroscience↗

bioRxiv2020

White matter connectivity of uncinate fasciculus and inferior fronto-occipital fasciculus: A possible early biomarker for callous-unemotional behaviors in young children with ADHD

BackgroundCallous-unemotional (CU) behaviors are important for identifying severe patterns of conduct problems (CP). One major fiber tract implicated in the development of CP is the uncinate fasciculus (UF), which connects amygdala and orbitofrontal cortex (OFC). The goals of the current study were to 1) explore differences in the white matter microstructure in the UF and other major fiber tracks (inferior longitudinal fasciculus [ILF], inferior fronto-occipital fasciculus [IFOF], cingulum, and corticospinal tract [CST]) between young typically developing (TD) children and those with Attention-Deficit/Hyperactivity Disorder (ADHD), and 2) explore, within the ADHD group, whether individual differences in these white matter microstructures relate to co-occurring CP and CU behaviors, respectively. MethodsParticipants included 198 young children (78% boys, Mage = 4.95 years; 80% Latinx; 49% TD). CU behaviors and CP were measured via a combination of teacher/parent ratings. Non-invasive diffusion-weighted imaging (DWI) was used to measure fractional anisotropy (FA), an indirect indicator of white matter properties. ResultsRelative to TD children, children with ADHD had reduced FA on four out of the five fiber tracks we examined (except for cingulum). Within the ADHD group, no associations were found between CP and reduced white matter integrity across any of the fiber tracks examined. However, we found that even after accounting for CP and a host of covariates including whole brain FA, CU behaviors were independently related to reduced FA in bilateral UF and left IFOF. ConclusionsThe bilateral UF and IFOF may be a biomarker of CU behaviors, even in very young children.

neuroscience↗

bioRxiv2020

In vivo Restricted-Diffusion Imaging (RDI) is sensitive to differences in axonal density in typical children and adults

BackgroundThe ability to dissociate axonal density in vivo from other microstructural properties of white matter is important for the diagnosis and treatment of neurologic disease, and new methods to do so are being developed. We investigated one such method-restricted diffusion imaging (RDI)-to see whether it can more accurately replicate histological axonal density patterns in the corpus callosum (CC) of adults and children compared to diffusion tensor imaging (DTI), neurite orientation dispersion and density imaging (NODDI), and generalized q-sampling imaging (GQI) methods. To do so, we compared known axonal density patterns defined by histology to to diffusion-weighted imaging (DWI) scans of 840 healthy 20- to 40-year-old adults, and, in a replication and extension, to DWI scans of 129 typically developing 7-month-old to 18-year-old children and adolescents. Contrast analyses were used to to compare pattern similarities between the in-vivo metric and previously-published histological density models. We found that RDI was effective at mapping axonal density of small (Cohens d= 2.60) and large fiber sizes (Cohens d= 2.84) in adults. The same pattern was observed in the developing sample (Cohens d= 3.09 and 3.78, respectively). Other metrics, notably NODDIs intracellular volume fraction (ICVF), were also sensitive to differences in axonal density across the longitudinal axis of the CC. In conclusion, the study showed that RDI is effective at measuring axonal density of small and large axons in adults and children, with both single- and multi-shell acquisition DWI data. Its effectiveness and availability to be used on standard as well as advanced DWI acquisitions makes it a promising method in clinical settings.

neuroscience↗

bioRxiv2018

The frontal aslant tract (FAT) and its role in speech, language and executive function

In this review, we examine the structural connectivity of a recently-identified fiber pathway, the frontal aslant tract (FAT), and explore its function. We first review structural connectivity studies using tract-tracing methods in non-human primates, and diffusion-weighted imaging and electrostimulation in humans. These studies suggest a monosynaptic connection exists between the lateral inferior frontal gyrus and the pre-supplementary and supplementary motor areas of the medial superior frontal gyrus. This connection is termed the FAT. We then review research on the left FATs putative role in supporting speech and language function, with particular focus on speech initiation, stuttering and verbal fluency. Next, we review research on the right FATs putative role supporting executive function, namely inhibitory control and conflict monitoring for action. We summarize the extant body of empirical work by suggesting that the FAT plays a domain general role in the planning, timing, and coordination of sequential motor movements through the resolution of competition among potential motor plans. However, we also propose some domain specialization across the hemispheres. On the left hemisphere, the circuit is proposed to be specialized for speech actions. On the right hemisphere, the circuit is proposed to be specialized for general action control of the organism, especially in the visuo-spatial domain. We close the review with a discussion of the clinical significance of the FAT, and suggestions for further research on the pathway.\n\nHighlightsO_LIThe frontal aslant tract (FAT) is a recently identified fiber pathway\nC_LIO_LIIt connects inferior frontal gyrus with medial frontal motor areas\nC_LIO_LIThe left FAT has been associated with speech and language function\nC_LIO_LIThe right FAT has been associated with inhibitory control\nC_LIO_LIBoth FAT pathways may function in sequential motor planning\nC_LI

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bioRxiv2017

Laterality of the frontal aslant tract (FAT) explains externalizing behaviors through its association with executive function.

We investigated the development of a recently-identified white matter pathway, the frontal aslant tract (FAT) and its association to executive function and externalizing behaviors in a sample of 129 neurotypical children ranging in age from 7 months to 19-years. We found that the FAT could be tracked in 92% of those children, and that the pathway showed age-related differences into adulthood. The change in white matter microstructure was very rapid until about 6-years, and then plateaued, only to show age-related increases again after the age of 11-years. In a subset of those children (5-18-years; n = 70), left laterality of the microstructural properties of the FAT was associated with greater attention problems as measured by the Child Behavior Checklist (CBCL). However, this relationship was fully mediated by higher executive dysfunction as measured by the Behavior Rating Inventory of Executive Function (BRIEF). This relationship was specific to the FAT--we found no relationship between laterality of the white matter of the brain in general and attention problems, or executive function. These findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.\n\nSignificance StatementTo investigate the function of a recently-identified white matter fiber pathway, the frontal aslant tract (FAT), we tracked the pathway in 129 typically developing children using diffusion-weighted magnetic resonance imaging (DW-MRI). We then examined whether laterality of the tract is associated with attention problems and executive function. We found that reduced right laterality of the tract was associated with greater executive dysfunction, which predicted increased reports of attention problems. The findings suggest that the degree to which the developing brain favors a right lateralized structural dominance of the FAT is directly associated with executive function and attention. This novel finding provides a new potential structural biomarker to assess attention deficit hyperactivity disorder (ADHD) and associated executive dysfunction during development.

neuroscience↗