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Intermittent theta burst stimulation (iTBS) is a well-established treatment for major depressive disorder (MDD), but predicting clinical outcomes remains challenging. Heart rate deceleration induced by iTBS has emerged as a potential biomarker for treatment response, yet the role of white matter (WM) properties in mediating these effects is largely unexplored. In this quadruple-blind, crossover study, we investigated the relationship between WM microstructure, iTBS-driven heart rate modulation, and antidepressant effects. Using correlational tractography, we focused on four major WM tracts—the cingulum, fornix, superior longitudinal fasciculus, and uncinate fasciculus—to examine short-term microstructural changes in relation to therapeutic outcomes. At baseline, findings revealed that fractional anisotropy (FA) in the fornix and right dorsal cingulum was negatively correlated with heart rate deceleration, while radial and mean diffusivity (MD, RD) in the fornix were positively correlated. In the right ventral cingulum, FA showed a positively correlation, while MD and RD were negatively correlated with symptom improvement. Longitudinally, FA increases in the left cingulum were significantly associated with greater symptom alleviation post-treatment. Notably, the correlation between iTBS-induced heart rate modulations and clinical improvement after six weeks, previously demonstrated in this cohort, was identified, while WM microstructural properties in the fornix and cingulum demonstrated predictive value for both heart rate modulation and treatment response. WM changes in the cingulum, evident as early as four weeks, highlight its unique neuroplasticity potential along iTBS intervention. Together, these findings provide novel insights into the structural connectivity patterns influencing iTBS outcomes, offering a novel foundation for more personalized therapeutic strategies in MDD.

Deep brain stimulation (DBS) to the fornix is an investigational treatment for patients with mild Alzheimer’s Disease. Outcomes from randomized clinical trials have shown that cognitive function improved in some patients but deteriorated in others. This could be explained by variance in electrode placement leading to differential engagement of neural circuits. To investigate this, we performed a post-hoc analysis on a multi-center cohort of 46 patients with DBS to the fornix (NCT00658125, NCT01608061). Using normative structural and functional connectivity data, we found that stimulation of the circuit of Papez and stria terminalis robustly associated with cognitive improvement ( R  = 0.53, p  < 0.001). On a local level, the optimal stimulation site resided at the direct interface between these structures ( R  = 0.48, p  < 0.001). Finally, modulating specific distributed brain networks related to memory accounted for optimal outcomes ( R  = 0.48, p  < 0.001). Findings were robust to multiple cross-validation designs and may define an optimal network target that could refine DBS surgery and programming. Deep brain stimulation has been investigated as a potential treatment for cognitive impairments in Alzheimer’s disease. Here the authors carry out post hoc analysis of multi-center cohorts to investigate the anatomical and functional correlates of effective deep brain stimulation, and find that stimulating circuit of Papez, fornix and bed nucleus of the stria terminalis, and a multi-region functional network, were associated with clinical improvement.

A tool was developed to automatically segment several subcortical limbic structures (nucleus accumbens, basal forebrain, septal nuclei, hypothalamus without mammillary bodies, the mammillary bodies, and fornix) using only a T1-weighted MRI as input. This tool fills an unmet need as there are few, if any, publicly available tools to segment these clinically relevant structures. A U-Net with spatial, intensity, contrast, and noise augmentation was trained using 39 manually labeled MRI data sets. In general, the Dice scores, true positive rates, false discovery rates, and manual-automatic volume correlation were very good relative to comparable tools for other structures. A diverse data set of 698 subjects were segmented using the tool; evaluation of the resulting labelings showed that the tool failed in less than 1% of cases. Test-retest reliability of the tool was excellent. The automatically segmented volume of all structures except mammillary bodies showed effectiveness at detecting either clinical AD effects, age effects, or both. This tool will be publicly released with FreeSurfer (surfer.nmr.mgh.harvard.edu/fswiki/ScLimbic). Together with the other cortical and subcortical limbic segmentations, this tool will allow FreeSurfer to provide a comprehensive view of the limbic system in an automated way.

Recently, much attention has been focused on the definition and structure of the hippocampus and its subfields, while the projections from the hippocampus have been relatively understudied. Here, we derive a reliable protocol for manual segmentation of hippocampal white matter regions (alveus, fimbria, and fornix) using high-resolution magnetic resonance images that are complementary to our previous definitions of the hippocampal subfields, both of which are freely available at https://github.com/cobralab/atlases. Our segmentation methods demonstrated high inter- and intra-rater reliability, were validated as inputs in automated segmentation, and were used to analyze the trajectory of these regions in both healthy aging (OASIS), and Alzheimer's disease (AD) and mild cognitive impairment (MCI; using ADNI). We observed significant bilateral decreases in the fornix in healthy aging while the alveus and cornu ammonis (CA) 1 were well preserved (all p's<0.006). MCI and AD demonstrated significant decreases in fimbriae and fornices. Many hippocampal subfields exhibited decreased volume in both MCI and AD, yet no significant differences were found between MCI and AD cohorts themselves. Our results suggest a neuroprotective or compensatory role for the alveus and CA1 in healthy aging and suggest that an improved understanding of the volumetric trajectories of these structures is required. •Novel high-resolution manual segmentation of human alveus, fimbria, and fornix.•Validation (precision and accuracy) of manual atlases for use in automatic segmentation.•Application of automatic segmentation on AD/MCI and healthy aging datasets.•Results suggest neuroprotective role for alveus and hippocampal CA1 region.

•Mesoscale mapping of connectivity in the human hippocampus.•Mapping of fimbrial fibers onto hippocampal substructures.•Mapping of inter- and translamellar networks in the hippocampus.•Dissection of 50 individual pathways between the head and body subregions.•Identification of 12 separate lamellae in the body of the hippocampus. The human hippocampus is essential to cognition and emotional processing. Its function is defined by its connectivity. Although some pathways have been well-established, our knowledge about anterior-posterior connectivity and the distribution of fibers from major fiber bundles remains limited. Mesoscale (250 μm isotropic acquisition, upsampled to 125 μm) resolution MR images of the human temporal lobe afforded a detailed visualization of fiber tracts, including those that related anterior-posterior substructures defined as subregions (head, body, tail) and subfields (cornu ammonis 1–3, dentate gyrus) of the hippocampus. Fifty pathways were dissected between the head and body, highlighting an intricate mesh of connectivity between these two subregions. Along the body subregion, 12 lamellae were identified based on morphology and the presence of interlamellar fibers that appear to connect neighboring lamellae at the edge of the external limb of the granule cell layer (GCL). Translamellar fibers (i.e. longitudinal fibers crossing more than 2 lamellae) were also evident at the edge of the internal limb of the GCL. The dentate gyrus of the body was the main site of connectivity with the fimbria. Unique pathways were dissected within the fimbria that connected the body of the hippocampus with the amygdala and the temporal pole. A topographical segregation within the fimbria was determined by fibers’ hippocampal origin, illustrating the importance of mapping the spatial distribution of fibers. Elucidating the detailed structural connectivity of the hippocampus is crucial to develop better diagnostic markers of neurological and psychiatric conditions, as well as to devise novel surgical interventions.

Aims Repetitive transcranial magnetic stimulation (rTMS) could improve the clinical manifestations in Alzheimer's disease (AD), but its impact on deep brain tissue related to memory remains unclear. This study explored whether rTMS targeting cortical gray matter could regulate the white matter (WM) and exert modulatory effects on the network through WM bundles. Methods Seventy‐three AD patients underwent 14‐day rTMS over the left dorsolateral prefrontal cortex (44 real, 25 sham). Granger causality analysis assessed changes in effective connectivity (EC) between the fornix and whole‐brain voxels. Furthermore, the effects of rTMS treatment on fiber tracking parameters were analyzed. Results After rTMS therapy, patients with AD showed increased EC based on fornix in the real‐stimulation group. Functional network projections indicated that these clusters belonged to the frontoparietal network, the somatomotor network, as well as three white matter networks. Additionally, increased EC associated with fornix exhibited lateralization on the right side. Diffusion tensor imaging results showed no significant differences after the 14‐day rTMS treatment. Conclusion In conclusion, a 14‐day rTMS treatment in AD could regulate fornical function by increasing cortical‐fornix EC, indicating neuroplasticity changes in response to therapy. Trial Registration Chinese Clinical Trial Registry (https://www.chictr.org.cn/index.html; ChiCTR2200062564) We enrolled Alzheimer's disease participants who received 14‐day repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (44 real rTMS, 25 sham). Real rTMS enhanced fornix‐based connectivity to frontoparietal, somatomotor, and white matter networks, highlighting the fornix as a mediator and potential biomarker of therapeutic response.

Aging leads to gray and white matter decline but their causation remains unclear. We explored two classes of models of age and dementia risk related brain changes. The first class of models emphasises the importance of gray matter: age and risk-related processes cause neurodegeneration and this causes damage in associated white matter tracts. The second class of models reverses the direction of causation: aging and risk factors cause white matter damage and this leads to gray matter damage. We compared these models with linear mediation analysis and quantitative MRI indices (from diffusion, quantitative magnetization transfer and relaxometry imaging) of tissue properties in two limbic structures implicated in age-related memory decline: the hippocampus and the fornix in 166 asymptomatic individuals (aged 38–71 years). Aging was associated with apparent glia but not neurite density damage in the fornix and the hippocampus. Mediation analysis supported white matter damage causing gray matter decline; controlling for fornix glia damage, the correlations between age and hippocampal damage disappear, but not vice versa . Fornix and hippocampal differences were both associated with reductions in episodic memory performance. These results suggest that fornix white matter glia damage may cause hippocampal gray matter damage during age-dependent limbic decline.

Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38–71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and kf] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and kf, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and kf, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD. •Central adiposity is linked to apparent myelin/inflammatory damage in the fornix.•Central adiposity is not linked to differences in apparent neurite microstructure.•Men were more centrally obese and had higher visceral fat fractions than women.•In women, age mediated the correlation between visceral fat and fornix myelin.•In men, adipokines mediated the correlation between WHR and fornix myelin.

Multivariate biomarkers are needed for detecting Alzheimer's disease (AD), understanding its etiology, and quantifying the effect of therapies. Mouse models provide opportunities to study characteristics of AD in well-controlled environments that can help facilitate development of early interventions. The CVN-AD mouse model replicates multiple AD hallmark pathologies, and we identified multivariate biomarkers characterizing a brain circuit disruption predictive of cognitive decline. In vivo and ex vivo magnetic resonance imaging (MRI) revealed that CVN-AD mice replicate the hippocampal atrophy (6%), characteristic of humans with AD, and also present changes in subcortical areas. The largest effect was in the fornix (23% smaller), which connects the septum, hippocampus, and hypothalamus. In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%) and axial diffusivity (2%), in detecting pathological changes. These findings were strengthened by optical microscopy and ultrastructural analyses. Ultrastructual analysis provided estimates of axonal density, diameters, and myelination—through the g-ratio, defined as the ratio between the axonal diameter, and the diameter of the axon plus the myelin sheath. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller g-ratios). CD68 staining showed that white matter pathology could be secondary to neuronal degeneration, or due to direct microglial attack. In conclusion, these findings strengthen the hypothesis that the fornix plays a role in AD, and can be used as a disease biomarker and as a target for therapy. [Display omitted] •We report white matter changes in the fimbria/fornix of the CVN-AD mouse model, supporting that white matter pathology plays a role in AD•In vivo and ex vivo MRI revealed that CVN-AD mice present hippocampal atrophy (6%), characteristic of humans with AD, as well as in subcortical areas, and white matter tracts. The largest effect was in the fornix (23% smaller).•In characterizing the fornix with diffusion tensor imaging, fractional anisotropy was most sensitive (20% reduction), followed by radial (15%), and axial diffusivity (2%) in detecting pathological changes.•Optical microscopy and ultrastructural analyses confirmed white matter pathology in CVN-AD mice. The fornix had reduced axonal density (47% fewer), axonal degeneration (13% larger axons), and abnormal myelination (1.5% smaller G ratios).•Our findings strengthen the hypothesis that the fornix plays a role in AD progression, and can be used both as a biomarker, and as a target for therapy.

INTRODUCTION Deep brain stimulation of the fornix (fx‐DBS) is being investigated for treatment of Alzheimer's disease (AD). The therapy aims at alleviating memory and cognitive circuit dysfunction. In preclinical models of AD, electrical stimulation of the memory circuit has demonstrated a possible disease‐modifying potential. Here we examined changes resulting from fx‐DBS in hippocampal atrophy and amyloid accumulation in AD patients with fx‐DBS. METHODS Repeated magnetic resonance imaging and positron emission tomography (PET) images acquired over the course of 12 months were used to assess changes in hippocampal volume in 36 ADvance trial patients compared to 40 matched untreated AD patients from the Alzheimer's Disease Neuroimaging Initiative, and in 10 separate patients with repeated flutemetamol PET and cerebrospinal fluid (CSF) markers. RESULTS We observed a reduction of hippocampal atrophy and amyloid beta (Aβ) PET binding, and an increase in the CSF Aβ/total‐tau ratio in DBS patients. DISCUSSION These findings highlight the potential of fornix deep brain stimulation to modify AD biomarkers and possibly progression in some patients. Highlights Fornix deep brain stimulation (fx‐DBS) is being investigated to treat Alzheimer's disease (AD). Results show that fx‐DBS modifies imaging and cerebrospinal fluid (CSF) markers. It reduces hippocampal atrophy and increases the amyloid beta/total‐tau CSF ratio. These findings highlight the potential of fx‐DBS to modify AD.