Re-wiring the brain: Increased functional connectivity within primary somatosensory cortex following synchronous co-activation

AbstractThe primary somatosensory cortex shows precise topographical organisation, but can be quickly modified by alterations to sensory inputs. Temporally correlated sensory inputs to the digits can result in the merging of digit representations on the cortical surface. Underlying mechanisms driving these changes are unclear but the strengthening of intra-cortical synaptic connections via Hebbian mechanisms has been suggested. We use fMRI measures of temporal coherence to infer alterations in the relative strength of neuronal connections between digit regions 2 and 4 following 3hours of synchronous and asynchronous co-activation. Following synchronous co-activation we find a 20% increase in temporal coherence of the fMRI signal (p=0.0004). No significant change is seen following asynchronous co-activation suggesting that temporal coincidence between the two digit inputs during co-activation is driving this coherence change. In line with previous work we also find a trend towards reduced separation of the digit representations following synchronous co-activation and significantly increased separation for the asynchronous case. Increased coherence is significantly correlated with reduced digit separation for the synchronous case. This study shows that passive synchronous stimulation to the digits strengthens the underlying cortical connections between the digit regions in only a few hours, and that this mechanism may be related to topographical re-organisation

Occult Cerebrovascular Disease and Late-Onset Epilepsy: Could Loss of Neurovascular Unit Integrity Be a Viable Model?

Late-onset epilepsy (LOE) first occurs after 60 years of age and may be due to occult cerebrovascular disease (CVD) which confers an increased risk of stroke. However, patients with late-onset epilepsy are not currently consistently investigated or treated for cerebrovascular risk factors. We discuss how abnormalities of neurovascular unit function, namely, changes in regional cerebral blood flow and blood brain barrier disruption, may be caused by occult cerebrovascular disease but present clinically as late-onset epilepsy. We describe novel magnetic resonance imaging methods to detect abnormal neurovascular unit function in subjects with LOE and controls. We hypothesise that occult CVD may cause LOE as a result of neurovascular unit dysfunction

Seizures in the context of occult cerebrovascular disease

There is an important bidirectional relationship between seizures and cerebrovascular disease (CVD). Aside from poststroke epilepsy, Occult CVD is an important cause of late-onset seizures (LOS) and late-onset epilepsy (LOE). Late-onset seizures/LOE are associated with a threefold increased risk of subsequent clinical stroke. This relationship exists not only in later life, but with ‘late-onset’ seizures or epilepsy occurring from the fourth decade of life onwards. There is increasing evidence for the importance of hypertension and cerebral small vessel disease (SVD) in epileptogenesis, but there is a considerable need for further work to elucidate underlying mechanisms. There may be a disproportionately increased risk of intracerebral hemorrhage (ICH) after LOS/LOE; this too requires further study. There is also a bidirectional relationship between LOS/LOE and cognitive impairment/dementia: it is likely that there are important interactions between vascular and neurodegenerative pathological processes mediating LOE, stroke, and dementia. There is a pressing need for better epidemiological and natural history data as well as elucidation of epileptogenic mechanisms, in order to progress our understanding and to better inform clinical practice

Structural and physiological neurovascular changes in idiopathic Parkinson's disease and its clinical phenotypes

Neurovascular changes are likely to interact importantly with the neurodegenerative process in idiopathic Parkinson's disease (IPD). Markers of neurovascular status (NVS) include white matter lesion (WML) burden and arterial spin labelling (ASL) measurements of cerebral blood flow (CBF) and arterial arrival time (AAT). We investigated NVS in IPD, including an analysis of IPD clinical phenotypes, by comparison with two control groups, one with a history of clinical cerebrovascular disease (CVD) (control positive, CP) and one without CVD (control negative, CN). Fifty-one patients with IPD (mean age 69.0 ± 7.7 years) (21 tremor dominant (TD), 24 postural instability and gait disorder (PIGD) and six intermediates), 18 CP (mean age 70.1 ± 8.0 years) and 34 CN subjects (mean age 67.4 ± 7.6 years) completed a 3T MRI scan protocol including T2-weighted fluid-attenuated inversion recovery (FLAIR) and ASL. IPD patients showed diffuse regions of significantly prolonged AAT, small regions of lower CBF and greater WML burden by comparison with CN subjects. TD patients showed lower WML volume by comparison with PIGD patients. These imaging data thus show altered NVS in IPD, with some evidence for IPD phenotype-specific differences

Cued memory reactivation during slow-wave sleep promotes explicit knowledge of a motor sequence

Memories are gradually consolidated after initial encoding, and this can sometimes lead to a transition from implicit to explicit knowledge. The exact physiological processes underlying this reorganization remain unclear. Here, we used a serial reaction time task to determine whether targeted memory reactivation (TMR) of specific memory traces during slow-wave sleep promotes the emergence of explicit knowledge. Human participants learned two 12-item sequences of button presses (A and B). These differed in both cue order and in the auditory tones associated with each of the four fingers (one sequence had four higher-pitched tones). Subsequent overnight sleep was monitored, and the tones associated with one learned sequence were replayed during slow-wave sleep. After waking, participants demonstrated greater explicit knowledge (p = 0.005) and more improved procedural skill (p = 0.04) for the cued sequence relative to the uncued sequence. Furthermore, fast spindles (13.5–15 Hz) at task-related motor regions predicted overnight enhancement in procedural skill (r = 0.71, p = 0.01). Auditory cues had no effect on post-sleep memory performance in a control group who received TMR before sleep. These findings suggest that TMR during sleep can alter memory representations and promote the emergence of explicit knowledge, supporting the notion that reactivation during sleep is a key mechanism in this process

Water-exchange MRI detects subtle blood-brain barrier breakdown in Alzheimer's disease rats

Blood-brain barrier (BBB) breakdown has been hypothesized to play a key role in the onset and progression of Alzheimer's disease (AD). However, the question of whether AD itself contributes to loss of BBB integrity is still uncertain, as many in-vivo studies have failed to detect signs of AD-related BBB breakdown. We hypothesize AD-related BBB damage is subtle, and that these negative results arise from a lack of measurement sensitivity. With the aim of developing a more sensitive measure of BBB breakdown, we have designed a novel MRI scanning protocol to quantify the trans-BBB exchange of endogenous water. Using this method, we detect increased BBB water permeability in a rat model of AD that is associated with reduced expression of the tight junction protein occludin. BBB permeability to MRI contrast agent, assessed using dynamic contrast-enhanced (DCE)-MRI, did not differ between transgenic and wild-type animals and was uncorrelated with occludin expression. Our data supports the occurrence of AD-related BBB breakdown, and indicates that such BBB pathology is subtle and may be undetectable using existing ‘tracer leakage’ methods. Our validated water-exchange MRI method provides a new powerful tool with which to study BBB damage in-vivo

Blood-brain barrier water exchange measurements using FEXI: Impact of modeling paradigm and relaxation time effects

PURPOSE: To evaluate potential modeling paradigms and the impact of relaxation time effects on human blood-brain barrier (BBB) water exchange measurements using FEXI (BBB-FEXI), and to quantify the accuracy, precision, and repeatability of BBB-FEXI exchange rate estimates at 3 T. METHODS: Three modeling paradigms were evaluated: (i) the apparent exchange rate (AXR) model; (ii) a two-compartment model (2CM) explicitly representing intra- and extravascular signal components, and (iii) a two-compartment model additionally accounting for finite compartmental T1 and T2 relaxation times (2CMr). Each model had three free parameters. Simulations quantified biases introduced by the assumption of infinite relaxation times in the AXR and 2CM models, as well as the accuracy and precision of all three models. The scan–rescan repeatability of all paradigms was quantified for the first time in vivo in 10 healthy volunteers (age range 23–52 years; five female) RESULTS: The assumption of infinite relaxation times yielded exchange rate errors in simulations up to 42%/14% in the AXR/2CM models, respectively. Accuracy was highest in the compartmental models; precision was best in the AXR model. Scan–rescan repeatability in vivo was good for all models, with negligible bias and repeatability coefficients in grey matter of RCAXR = 0.43 s −1, RC2CM = 0.51 s −1, and RC2CMr = 0.61 s −1. CONCLUSION: Compartmental modelling of BBB-FEXI signals can provide accurate and repeatable measurements of BBB water exchange; however, relaxation time and partial volume effects may cause model-dependent biases

Alzheimer's disease pathology is associated with earlier alterations to blood–brain barrier water permeability compared with healthy ageing in TgF344‐AD rats

From Wiley via Jisc Publications RouterHistory: received 2020-11-05, rev-recd 2021-02-06, accepted 2021-02-26, pub-electronic 2021-03-15, pub-print 2021-07Article version: VoRPublication status: PublishedFunder: Biotechnology and Biological Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000268; Grant(s): BB/F011350Funder: Engineering and Physical Sciences Research Council; Id: http://dx.doi.org/10.13039/501100000266; Grant(s): EP/M005909/1Funder: European Union’s Seventh Framework Programme; Grant(s): FP7/2007‐2013, HEALTH‐F2‐2011‐278850, HEALTH‐F2‐2011‐278850The effects of Alzheimer's disease (AD) and ageing on blood–brain barrier (BBB) breakdown are investigated in TgF344‐AD and wild‐type rats aged 13, 18 and 21 months. Permeability surface area products of the BBB to water (PSw) and gadolinium‐based contrast agent (PSg) were measured in grey matter using multiflip angle multiecho dynamic contrast‐enhanced MRI. At 13 months of age, there was no significant difference in PSw between TgF344‐AD and wild‐types (p = 0.82). Between 13 and 18 months, PSw increased in TgF344‐AD rats (p = 0.027), but not in wild‐types (p = 0.99), leading to significantly higher PSw in TgF344‐AD rats at 18 months, as previously reported (p = 0.012). Between 18 and 21 months, PSw values increased in wild‐types (p = 0.050), but not in TgF344‐AD rats (p = 0.50). These results indicate that BBB water permeability is affected by both AD pathology and ageing, but that changes occur earlier in the presence of AD pathology. There were no significant genotype or ageing effects on PSg (p > 0.05). In conclusion, we detected increases in BBB water permeability with age in TgF344‐AD and wild‐type rats, and found that changes occurred at an earlier age in rats with AD pathology

Ambiguous loss and incomplete abduction narratives in Kosovo

Ten mothers of men and boys who were abducted and listed as missing during the war in Kosovo in 1998/1999 were interviewed in Kosovo in the spring of 2012. Although the missing are presumed dead by the authorities, the mothers continue to live in a state of emotional ambiguity where a presumption of death is balanced with the hope of being reunited. In the absence of absolute proof, finding the remains of their loved ones becomes a major preoccupation. Using a social phenomenological approach, this study explored the social and political complexities existing within the life-world of these women. The findings suggest that they live in a continual state of psychological distress, and even when remains are returned, the unknown elements of the narrative of their abduction and murder only add to their distress and force many into self-imposed emotional exile away from community and close family

A Systematic Review of Glucose Transport Alterations in Alzheimer's Disease

From Frontiers via Jisc Publications RouterHistory: collection 2021, received 2021-01-12, accepted 2021-04-22, epub 2021-05-20Publication status: PublishedIntroduction: Alzheimer's disease (AD) is characterized by cerebral glucose hypometabolism. Hypometabolism may be partly due to reduced glucose transport at the blood-brain barrier (BBB) and across astrocytic and neuronal cell membranes. Glucose transporters (GLUTs) are integral membrane proteins responsible for moving glucose from the bloodstream to parenchymal cells where it is metabolized, and evidence indicates vascular and non-vascular GLUTs are altered in AD brains, a process which could starve the brain of glucose and accelerate cognitive decline. Here we review the literature on glucose transport alterations in AD from human and rodent studies. Methods: Literature published between 1st January 1946 and 1st November 2020 within EMBASE and MEDLINE databases was searched for the terms “glucose transporters” AND “Alzheimer's disease”. Human and rodent studies were included while reviews, letters, and in-vitro studies were excluded. Results: Forty-three studies fitting the inclusion criteria were identified, covering human (23 studies) and rodent (20 studies). Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD