Subiculum-BNST structural connectivity in humans and macaques.

Invasive tract-tracing studies in rodents implicate a direct connection between the subiculum and bed nucleus of the stria terminalis (BNST) as a key component of neural pathways mediating hippocampal regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis. A clear characterisation of the connections linking the subiculum and BNST in humans and non-human primates is lacking. To address this, we first delineated the projections from the subiculum to the BNST using anterograde tracers injected into macaque monkeys, revealing evidence for a monosynaptic subiculum-BNST projection involving the fornix. Second, we used in vivo diffusion MRI tractography in macaques and humans to demonstrate substantial subiculum complex connectivity to the BNST in both species. This connection was primarily carried by the fornix, with additional connectivity via the amygdala, consistent with rodent anatomy. Third, utilising the twin-based nature of our human sample, we found that microstructural properties of these tracts were moderately heritable (h2 ∼ 0.5). In a final analysis, we found no evidence of any significant association between subiculum complex-BNST tract microstructure and indices of perceived stress/dispositional negativity and alcohol use, derived from principal component analysis decomposition of self-report data. Our findings address a key translational gap in our knowledge of the neurocircuitry regulating stress.

The Effectiveness of Virtual Reality Interventions for Improvement of Neurocognitive Performance After Traumatic Brain Injury: A Systematic Review.

OBJECTIVE: To evaluate current evidence for the effectiveness of virtual reality (VR) interventions in improving neurocognitive performance in individuals who have sustained a traumatic brain injury (TBI). METHODS: A systematic literature search across multiple databases (PubMed, EMBASE, Web of Science) for articles of relevance. Studies were evaluated according to study design, patient cohort, VR intervention, neurocognitive parameters assessed, and outcome. VR interventions were evaluated qualitatively with respect to methodology and extent of immersion and quantitatively with respect to intervention duration. OUTCOMES: Our search yielded 324 articles, of which only 13 studies including 132 patients with TBI met inclusion criteria. A wide range of VR interventions and cognitive outcome measures is reported. Cognitive measures included learning and memory, attention, executive function, community skills, problem solving, route learning, and attitudes about driving. Several studies (n = 10) reported statistically significant improvements in outcome, and 2 studies demonstrated successful translation to real-life performance. CONCLUSIONS: VR interventions hold significant potential for improving neurocognitive performance in patients with TBI. While there is some evidence for translation of gains to activities of daily living, further studies are required to confirm the validity of cognitive measures and reliable translation to real-life performance.

Interindividual variation in fornix microstructure and macrostructure is related to visual discrimination accuracy for scenes but not faces.

Transection of the nonhuman primate fornix has been shown to impair learning of configurations of spatial features and object-in-scene memory. Although damage to the human fornix also results in memory impairment, it is not known whether there is a preferential involvement of this white-matter tract in spatial learning, as implied by animal studies. Diffusion-weighted MR images were obtained from healthy participants who had completed versions of a task in which they made rapid same/different discriminations to two categories of highly visually similar stimuli: (1) virtual reality scene pairs; and (2) face pairs. Diffusion-MRI measures of white-matter microstructure [fractional anisotropy (FA) and mean diffusivity (MD)] and macrostructure (tissue volume fraction, f) were then extracted from the fornix of each participant, which had been reconstructed using a deterministic tractography protocol. Fornix MD and f measures correlated with scene, but not face, discrimination accuracy in both discrimination tasks. A complementary voxelwise analysis using tract-based spatial statistics suggested the crus of the fornix as a focus for this relationship. These findings extend previous reports of spatial learning impairments after fornix transection in nonhuman primates, critically highlighting the fornix as a source of interindividual variation in scene discrimination in humans.

The role of the pre-commissural fornix in episodic autobiographical memory and simulation.

Neuropsychological and functional magnetic resonance imaging evidence suggests that the ability to vividly remember our personal past, and imagine future scenarios, involves two closely connected regions: the hippocampus and ventromedial prefrontal cortex (vmPFC). Despite evidence of a direct anatomical connection from hippocampus to vmPFC, it is unknown whether hippocampal-vmPFC structural connectivity supports both past- and future-oriented episodic thinking. To address this, we applied a novel deterministic tractography protocol to diffusion-weighted magnetic resonance imaging (dMRI) data from a group of healthy young adult humans who undertook an adapted past-future autobiographical interview (portions of this data were published in Hodgetts et al., 2017a). This tractography protocol enabled distinct subdivisions of the fornix, detected previously in axonal tracer studies, to be reconstructed in vivo, namely the pre-commissural (connecting the hippocampus to vmPFC) and post-commissural (linking the hippocampus and medial diencephalon) fornix. As predicted, we found that inter-individual differences in pre-commissural - but not post-commissural - fornix microstructure (fractional anisotropy) were significantly correlated with the episodic richness of both past and future autobiographical narratives. Notably, these results held when controlling for non-episodic narrative content, verbal fluency, and grey matter volumes of the hippocampus and vmPFC. This study provides novel evidence that reconstructing events from one's personal past, and constructing possible future events, involves a distinct, structurally-instantiated hippocampal-vmPFC pathway.

Structural connections support emotional connections: Uncinate Fasciculus microstructure is related to the ability to decode facial emotion expressions.

The Uncinate Fasciculus (UF) is an association fibre tract connecting regions in the frontal and anterior temporal lobes. UF disruption is seen in several disorders associated with impaired social behaviour, but its functional role is unclear. Here we set out to test the hypothesis that the UF is important for facial expression processing, an ability fundamental to adaptive social behaviour. In two separate experiments in healthy adults, we used high-angular resolution diffusion-weighted imaging (HARDI) and constrained spherical deconvolution (CSD) tractography to virtually dissect the UF, plus a control tract (the corticospinal tract (CST)), and quantify, via fractional anisotropy (FA), individual differences in tract microstructure. In Experiment 1, participants completed the Reading the Mind in the Eyes Task (RMET), a well-validated assay of facial expression decoding. In Experiment 2, a different set of participants completed the RMET, plus an odd-emotion-out task of facial emotion discrimination. In both experiments, participants also completed a control odd-identity-out facial identity discrimination task. In Experiment 1, FA of the right-, but not the left-hemisphere, UF was significantly correlated with performance on the RMET task, specifically for emotional, but not neutral expressions. UF FA was not significantly correlated with facial identity discrimination performance. In Experiment 2, FA of the right-, but not left-hemisphere, UF was again significantly correlated with performance on emotional items from the RMET, together with performance on the facial emotion discrimination task. Again, no significant association was found between UF FA and facial identity discrimination performance. Our findings highlight the contribution of right-hemisphere UF microstructure to inter-individual variability in the ability to decode facial emotion expressions, and may explain why disruption of this pathway affects social behaviour.

Increased posterior default mode network activity and structural connectivity in young adult APOE-ε4 carriers: a multimodal imaging investigation.

Young adult APOE-ε4 carriers show increased activity in posterior regions of the default mode network (pDMN), but how this is related to structural connectivity is unknown. Thirty young adults (one half of whom were APOE-ε4 carriers; mean age 20 years) were scanned using both diffusion and functional magnetic resonance imaging. The parahippocampal cingulum bundle (PHCB)-which links the pDMN and the medial temporal lobe-was manually delineated in individual participants using deterministic tractography. Measures of tract microstructure (mean diffusivity and fractional anisotropy) were then extracted from these tract delineations. APOE-ε4 carriers had lower mean diffusivity and higher fractional anisotropy relative to noncarriers in PHCB, but not in a control tract (the inferior longitudinal fasciculus). Furthermore, PHCB microstructure was selectively associated with pDMN (and medial temporal lobe) activity during a scene discrimination task known to be sensitive to Alzheimer's disease. These findings are consistent with a lifespan view of Alzheimer's disease risk, where early-life, connectivity-related changes in specific, vulnerable "hubs" (e.g., pDMN) lead to increased neural activity. Critically, such changes may reflect reduced network efficiency/flexibility in APOE-ε4 carriers, which in itself may portend a faster decline in connectivity over the lifespan and ultimately trigger early amyloid-ß deposition in later life.

A protocol for a randomised controlled, double-blind feasibility trial investigating fluoxetine treatment in improving memory and learning impairments in patients with mesial temporal lobe epilepsy: Fluoxetine, Learning and Memory in Epilepsy (FLAME trial).

BACKGROUND: People with temporal lobe epilepsy (TLE) report significant problems with learning and memory. There are no effective therapies for combatting these problems in people with TLE, resulting in an unmet therapeutic need. The lack of treatment is, in part, due to a poor understanding of the neurobiology underlying these memory deficits. We know that hippocampal neurogenesis, a process believed to be important in learning and memory formation, is permanently reduced in chronic TLE, and this may go some way to explain the learning and memory impairments seen in people with TLE.The common anti-depressant drug fluoxetine has been shown to stimulate neurogenesis both in the healthy brain and in neurological diseases where neurogenesis is impaired. In an animal model of TLE, administration of fluoxetine was found to restore neurogenesis and improve learning on a complex spatial navigational task. We now want to test this effect in humans by investigating whether administration of fluoxetine to people with TLE can improve learning and memory. METHODS: This is a single-centre randomised controlled, double-blind feasibility trial. We plan to recruit 20 participants with a diagnosis of TLE and uni-lateral hippocampal sclerosis, confirmed by 3T MRI. Eligible participants will undergo baseline assessments of learning and memory prior to being randomised to either 20 mg/day fluoxetine or matching placebo for 60 days. Follow-up assessments will be conducted after 60 days of trial medication and then again at 60 days after cessation of trial medication. Feasibility will be assessed on measures of recruitment, retention and adherence against pre-determined criteria. DISCUSSION: This trial is designed to determine the feasibility of conducting a double-blind randomised controlled trial of fluoxetine for the treatment of learning and memory impairments in people with TLE. Data collected in this trial will inform the design and utility of any future efficacy trial involving fluoxetine for the treatment of learning and memory in people with TLE. TRIAL REGISTRATION: EudraCT 2014-005088-34, registered on May 18, 2015.

Distinct contributions of the fornix and inferior longitudinal fasciculus to episodic and semantic autobiographical memory.

Autobiographical memory (AM) is multifaceted, incorporating the vivid retrieval of contextual detail (episodic AM), together with semantic knowledge that infuses meaning and coherence into past events (semantic AM). While neuropsychological evidence highlights a role for the hippocampus and anterior temporal lobe (ATL) in episodic and semantic AM, respectively, it is unclear whether these constitute dissociable large-scale AM networks. We used high angular resolution diffusion-weighted imaging and constrained spherical deconvolution-based tractography to assess white matter microstructure in 27 healthy young adult participants who were asked to recall past experiences using word cues. Inter-individual variation in the microstructure of the fornix (the main hippocampal input/output pathway) related to the amount of episodic, but not semantic, detail in AMs - independent of memory age. Conversely, microstructure of the inferior longitudinal fasciculus, linking occipitotemporal regions with ATL, correlated with semantic, but not episodic, AMs. Further, these significant correlations remained when controlling for hippocampal and ATL grey matter volume, respectively. This striking correlational double dissociation supports the view that distinct, large-scale distributed brain circuits underpin context and concepts in AM.

Dissociable roles of the inferior longitudinal fasciculus and fornix in face and place perception.

We tested a novel hypothesis, generated from representational accounts of medial temporal lobe (MTL) function, that the major white matter tracts converging on perirhinal cortex (PrC) and hippocampus (HC) would be differentially involved in face and scene perception, respectively. Diffusion tensor imaging was applied in healthy participants alongside an odd-one-out paradigm sensitive to PrC and HC lesions in animals and humans. Microstructure of inferior longitudinal fasciculus (ILF, connecting occipital and ventro-anterior temporal lobe, including PrC) and fornix (the main HC input/output pathway) correlated with accuracy on odd-one-out judgements involving faces and scenes, respectively. Similarly, blood oxygen level-dependent (BOLD) response in PrC and HC, elicited during oddity judgements, was correlated with face and scene oddity performance, respectively. We also observed associations between ILF and fornix microstructure and category-selective BOLD response in PrC and HC, respectively. These striking three-way associations highlight functionally dissociable, structurally instantiated MTL neurocognitive networks for complex face and scene perception.