The tendency to show the renewal effect of extinction appears as an intra-individually stable, reproducible processing strategy associated with differential patterns of BOLD activation in hippocampus, iFG and vmPFC, as well as differential resting-state functional connectivity between prefrontal regions and the dorsal attention network. Also, pharmacological modulations of the noradrenergic system that influence attentional processing have partially different effects upon individuals with (REN) and without (NoREN) a propensity for renewal. However, it is as yet unknown whether REN and NoREN individuals differ regarding microstructural properties in attention-related white matter (WM) regions, and whether such differences are related to noradrenergic processing. In this diffusion tensor imaging (DTI) analysis we investigated the relation between microstructural properties of attention-related WM tracts and ABA renewal propensity, under conditions of noradrenergic stimulation by means of the noradrenergic reuptake inhibitor atomoxetine, compared to placebo. Fractional anisotropy (FA) was higher in participants with noradrenergic stimulation (ATO) compared to placebo (PLAC), the effect was predominantly left-lateralized and based on the comparison of ATO REN and PLAC REN participants. In REN participants of both treatment groups, FA in several WM tracts showed a positive correlation with the ABA renewal level, suggesting higher renewal levels were associated with higher microstructural integrity. These findings point towards a relation between microstructural properties of attention-related WM tracts and the propensity for renewal that is not specifically dependent on noradrenergic processing.

Neuroimaging studies have consistently demonstrated concurrent activation of the human precuneus and temporal pole (TP), both during resting-state conditions and various higher-order cognitive functions. However, the precise underlying structural connectivity between these brain regions remains uncertain despite significant advancements in neuroscience research. In this study, we investigated the connectivity of the precuneus and TP by employing parcellation-based fiber micro-dissections in human brains and fiber tractography techniques in a sample of 1065 human subjects and a sample of 41 rhesus macaques. Our results demonstrate the connectivity between the posterior precuneus area POS2 and the areas 35, 36, and TG of the TP via the fifth subcomponent of the cingulum (CB-V) also known as parahippocampal cingulum. This finding contributes to our understanding of the connections within the posteromedial cortices, facilitating a more comprehensive integration of anatomy and function in both normal and pathological brain processes. PRACTITIONER POINTS: Our investigation delves into the intricate architecture and connectivity patterns of subregions within the precuneus and temporal pole, filling a crucial gap in our knowledge. We revealed a direct axonal connection between the posterior precuneus (POS2) and specific areas (35, 35, and TG) of the temporal pole. The direct connections are part of the CB-V pathway and exhibit a significant association with the cingulum, SRF, forceps major, and ILF. Population-based human tractography and rhesus macaque fiber tractography showed consistent results that support micro-dissection outcomes.

Cognitive functions, such as learning and memory processes, depend on effective communication between brain regions which is facilitated by white matter tracts (WMT). We investigated the microstructural properties and the contribution of WMT to extinction learning and memory in a predictive learning task. Forty-two healthy participants completed an extinction learning paradigm without a fear component. We examined differences in microstructural properties using diffusion tensor imaging to identify underlying neural connectivity and structural correlates of extinction learning and their potential implications for the renewal effect. Participants with good acquisition performance exhibited higher fractional anisotropy (FA) in WMT including the bilateral inferior longitudinal fasciculus (ILF) and the right temporal part of the cingulum (CNG). This indicates enhanced connectivity and communication between brain regions relevant to learning and memory resulting in better learning performance. Our results suggest that successful acquisition and extinction performance were linked to enhanced structural connectivity. Lower radial diffusivity (RD) in the right ILF and right temporal part of the CNG was observed for participants with good acquisition learning performance. This observation suggests that learning difficulties associated with increased RD may potentially be due to less myelinated axons in relevant WMT. Also, participants with good acquisition performance were more likely to show a renewal effect. The results point towards a potential role of structural integrity in extinction-relevant WMT for acquisition and extinction.

Blast-related mild traumatic brain injury (BR mTBI) is a critical research area in recent combat veterans due to increased prevalence of survived blasts. Post-BR mTBI outcomes are highly heterogeneous and defining neurological differences may help in discrimination and prediction of cognitive outcomes. This study investigates whether white matter integrity, measured with diffusion tensor imaging (DTI), could influence how remote BR mTBI history is associated with executive control. The sample included 151 Veterans from the Minneapolis Veterans Affairs Medical Center who were administered a clinical/TBI assessment, neuropsychological battery, and DTI scan as part of a larger battery. From previous research, six white matter tracts were identified as having a putative relationship with blast severity: the cingulum, hippocampal cingulum, corticospinal tract, inferior fronto-occipital fasciculus, superior longitudinal fasciculus and uncinate. Fractional anisotropy (FA) of the a priori selected white matter tracts and report of BR mTBI were used as predictors of Trail-Making Test B (TMT-B) performance in a multiple linear regression model. Statistical analysis revealed that FA of the hippocampal cingulum moderated the association between report of at least one BR mTBI and poorer TMT-B performance (p < 0.008), such that lower FA value was associated with worse TMT-B outcomes in individuals with BR mTBI. No significant moderation existed for other selected tracts, and the effect was not observed with predictors aside from history of BR mTBI. Investigation at the individual-tract level may lead to a deeper understanding of neurological differences between blast-related and non-blast related injuries.

UNASSIGNED: Decreasing white matter integrity in limbic pathways including the fornix and cingulum have been reported in Alzheimer\'s disease (AD), although underlying mechanisms and potential sex differences remain understudied. We therefore sought to explore sex as a moderator of the effect of age on myelin water fraction (MWF), a measure of myelin content, in older adults without dementia (N = 52).
UNASSIGNED: Participants underwent neuropsychological evaluation and 3 T MRI at two research sites. Multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) quantified MWF in 3 a priori regions including the fornix, hippocampal cingulum (CgH), and cingulate cingulum (CgC). The California Verbal Learning Test-Second Edition assessed learning and delayed recall. Multiple linear regressions assessed for (1) interactions between age and sex on regional MWF and (2) associations of regional MWF and memory.
UNASSIGNED: (1) There was a significant age by sex interaction on MWF of the fornix (p = 0.002) and CgC (p = 0.005), but not the CgH (p = 0.192); as age increased, MWF decreased in women but not men. (2) Fornix MWF was associated with both learning and recall (ps < 0.01), but MWF of the two cingulum regions were not (p > 0.05). Results were unchanged when adjusting for hippocampal volume.
UNASSIGNED: The current work adds to the literature by illuminating sex differences in age-related myelin decline using a measure sensitive to myelin and may help facilitate detection of AD risk for women.

Previous Alzheimer\'s disease and related dementias (AD/ADRD) research studies have illustrated the significance of studying alterations in white matter (WM). Fewer studies have examined how WM integrity, measured with diffusion tensor imaging (DTI), is associated with volume of gray matter (GM) regions and measures of cognitive function in aged participants spanning the dementia continuum.
Magnetic resonance imaging and cognitive data were collected from 241 Boston University Alzheimer\'s Disease Research Center participants who spanned from cognitively normal controls to amnestic mild cognitive impairment to having dementia. Primary DTI tracts of interest were the cingulum ventral (CV) and cingulum dorsal (CD) pathways. GM regions of interest (ROIs) were in the medial temporal lobe (MTL), prefrontal cortex, and retrosplenial cortex. Analyses of covariance models were used to assess differences in WM integrity across groups (control, amnestic mild cognitive impairment, and dementia). Multiple linear regression models were used to assess associations between WM integrity and GM volume, and with measures of memory and executive function.
Differences in WM integrity were shown in both cingulum pathways in participants across the dementia continuum. Associations between WM integrity of both cingulum pathways and volume of selected GM ROIs were widespread. Functionally significant associations were found between WM of the CV pathway and memory, independent of MTL GM volume.
Differences in WM integrity of the cingulum bundle and surrounding GM ROI are likely related to the progression of AD/ADRD. Such differences should continue to be studied, particularly in association with memory performance.

UNASSIGNED: Subjective cognitive decline (SCD) with a positive amyloid burden has been recognized as the earliest clinical symptom of the preclinical phase of Alzheimers disease (AD), providing invaluable opportunities to improve our understanding of the natural history of AD and determine strategies for early therapeutic interventions.
UNASSIGNED: The microstructure of white matter in patients showing SCD in the preclinical phase of AD (SCD of pre-AD) was evaluated using diffusion images, and voxel-wise fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusivities were assessed and compared among participant groups. Significant clusters in the tracts were extracted to determine their associations with alterations in the cognitive domains.
UNASSIGNED: We found that individuals with SCD of pre-AD may have subclinical episodic memory impairment associated with the global amyloid burden. Meanwhile, we found significantly reduced FA and λ1 in the right cingulum (cingulate and hippocampus) in AD dementia, while significantly increased FA and decreased MD as well as λ23 in the SCD of pre-AD group in comparison with the HC group.
UNASSIGNED: In conclusion, increased white matter microstructural integrity in the right cingulum (cingulate and hippocampus) may indicate compensation for short-term episodic memory in individuals with SCD of pre-AD in comparison with individuals with AD and healthy elderly individuals.

The model of the four streams of the prefrontal cortex proposes 4 streams of information: motor through Brodmann area (BA) 8, emotion through BA 9, memory through BA 10, and emotional-related sensory through BA 11. Although there is a surge of functional data supporting these 4 streams within the PFC, the structural connectivity underlying these neural networks has not been fully clarified. Here we perform population-based high-definition tractography using an averaged template generated from data of 1,065 human healthy subjects acquired from the Human Connectome Project to further elucidate the structural organization of these regions. We report the structural connectivity of BA 8 with BA 6, BA 9 with the insula, BA 10 with the hippocampus, BA 11 with the temporal pole, and BA 11 with the amygdala. The 4 streams of the prefrontal cortex are subserved by a structural neural network encompassing fibers of the anterior part of the superior longitudinal fasciculus-I and II, corona radiata, cingulum, frontal aslant tract, and uncinate fasciculus. The identified neural network of the four streams of the PFC will allow the comprehensive analysis of these networks in normal and pathological brain function.

Adolescence is often characterized by sleep disturbances that can affect the development of white matter tracts implicated in affective and cognitive regulation, including the cingulate portion of the cingulum bundle (CGC) and the uncinate fasciculus (UF). These effects may be exacerbated in adolescents exposed to early life adversity (ELA). We examined the longitudinal relations between sleep problems and CGC and UF microstructure during adolescence and their relation to depressive symptoms as a function of exposure to ELA. We assessed self-reported sleep disturbances and depressive symptoms and acquired diffusion-weighted MRI scans twice: in early adolescence (9-13 years) and four years later (13-17 years) (N = 72 complete cases). Independent of ELA, higher initial levels and increases in sleep problems were related to increases in depressive symptoms. Further, increases in right CGC fractional anisotropy (FA) mediated the association between sleep problems and depressive symptoms for youth who experienced lower, but not higher, levels of ELA. In youth with higher ELA, higher initial levels of and steeper decreases in sleep problems were associated with greater decreases in right UF FA, but were unrelated to depressive symptoms. Our findings highlight the importance of sleep quality in shaping fronto-cingulate-limbic tract development and depressive symptoms during adolescence.

Brain maturation and neurological diseases are intricately linked to microstructural changes that inherently affect the brain\'s mechanical behavior. Animal models are frequently used to explore relative brain stiffness changes as a function of underlying microstructure. Here, we are using the cuprizone mouse model to study indentation-derived stiffness changes resulting from acute and chronic demyelination during a 15-week observation period. We focus on the corpus callosum, cingulum, and cortex which undergo different degrees of de- and remyelination and, therefore, result in region-specific stiffness changes. Mean stiffness of the corpus callosum starts at 1.1 ± 0.3 kPa in untreated mice, then cuprizone treatment causes stiffness to drop to 0.6 ± 0.1 kPa by week 3, temporarily increase to 0.9 ± 0.3 kPa by week 6, and ultimately stabilize around 0.7 ± 0.1 kPa by week 9 for the rest of the observation period. The cingulum starts at 3.2 ± 0.9 kPa, then drops to 1.6 ± 0.4 kPa by week 3, and then gradually stabilizes around 1.4 ± 0.3 kPa by week 9. Cortical stiffness exhibits less stiffness variations overall; it starts at 4.2 ± 1.3 kPa, drops to 2.4 ± 0.6 kPa by week 3, and stabilizes around 2.7 ± 0.9 kPa by week 6. We also assess the impact of tissue fixation on indentation-based mechanical tissue characterization. On the one hand, fixation drastically increases untreated mean tissue stiffness by a factor of 3.3 for the corpus callosum, 2.9 for the cingulum, and 3.6 for the cortex; on the other hand, fixation influences interregional stiffness ratios during demyelination, thus suggesting that fixation affects individual brain tissues differently. Lastly, we determine the spatial correlation between stiffness measurements and myelin density and observe a region-specific proportionality between myelin content and tissue stiffness. STATEMENT OF SIGNIFICANCE: Despite extensive work, the relationship between microstructure and mechanical behavior in the brain remains mostly unknown. Additionally, the existing variation of measurement results reported in literature requires in depth investigation of the impact of individual cell and protein populations on tissue stiffness and interregional stiffness ratios. Here, we used microindentation measurements to show that brain stiffness changes with myelin density in the cuprizone-based demyelination mouse model. Moreover, we explored the impact of tissue fixation prior to mechanical characterization because of conflicting results reported in literature. We observe that fixation has a distinctly different impact on our three regions of interest, thus causing region-specific tissue stiffening and, more importantly, changing interregional stiffness ratios.