Methylphenidate differentially alters corticostriatal connectivity after traumatic brain injury.

Traumatic brain injury commonly impairs attention and executive function, and disrupts the large-scale brain networks that support these cognitive functions. Abnormalities of functional connectivity are seen in corticostriatal networks, which are associated with executive dysfunction and damage to neuromodulatory catecholaminergic systems caused by head injury. Methylphenidate, a stimulant medication that increases extracellular dopamine and noradrenaline, can improve cognitive function following TBI. In this experimental medicine add-on study to a randomised, double-blind, placebo-controlled clinical trial, we test whether administration of methylphenidate alters corticostriatal network function and influences drug response. 43 moderate-severe traumatic brain injury patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. 28 patients were included in the neuropsychological and functional imaging analysis (4 females, mean age 40.9±12.7, range 20-65) and underwent functional MRI and neuropsychological assessment after each block. 123I-Ioflupane SPECT Dopamine Transporter (DAT) scans were performed, and specific binding ratios were extracted from caudate subdivisions. Functional connectivity and the relationship to cognition was compared between drug and placebo conditions. Methylphenidate increased caudate to anterior cingulate cortex functional connectivity compared to placebo and decreased connectivity from the caudate to default mode network. Connectivity within the default mode network was also decreased by methylphenidate administration and there was a significant relationship between caudate functional connectivity and DAT binding during methylphenidate administration. Methylphenidate significantly improved executive function in TBI patients, and this was associated with alterations in the relationship between executive function and right anterior caudate functional connectivity. Functional connectivity is strengthened to brain regions including the anterior cingulate that are activated when attention is focused externally. These results show that methylphenidate alters caudate interactions with cortical brain networks involved in executive control. In contrast, caudate functional connectivity reduces to default mode network regions involved in internally focused attention and that deactivate during tasks that require externally focused attention. These results suggest that the beneficial cognitive effects of methylphenidate may be mediated through its impact on the caudate. Methylphenidate differentially influences how the caudate interacts with large-scale functional brain networks that exhibit co-ordinated but distinct patterns of activity required for attentionally demanding tasks.

The human vestibular cortex: functional anatomy of OP2, its connectivity and the effect of vestibular disease.

Area OP2 in the posterior peri-sylvian cortex has been proposed to be the core human vestibular cortex. We investigated the functional anatomy of OP2 and adjacent areas (OP2+) using spatially constrained independent component analysis (ICA) of functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. Ten ICA-derived subregions were identified. OP2+ responses to vestibular and visual motion were analyzed in 17 controls and 17 right-sided vestibular neuritis patients who had previously undergone caloric and optokinetic stimulation during fMRI. In controls, a posterior part of right OP2+ showed: (i) direction-selective responses to visual motion and (ii) activation during caloric stimulation that correlated positively with perceived self-motion, and negatively with visual dependence and peak slow-phase nystagmus velocity. Patients showed abnormal OP2+ activity, with an absence of visual or caloric activation of the healthy ear and no correlations with vertigo or visual dependence-despite normal slow-phase nystagmus responses to caloric stimulation. Activity in a lateral part of right OP2+ correlated with chronic visually induced dizziness in patients. In summary, distinct functional subregions of right OP2+ show strong connectivity to other vestibular areas and a profile of caloric and visual responses, suggesting a central role for vestibular function in health and disease.

Pathological Slow-Wave Activity and Impaired Working Memory Binding in Post-Traumatic Amnesia.

Associative binding is key to normal memory function and is transiently disrupted during periods of post-traumatic amnesia (PTA) following traumatic brain injury (TBI). Electrophysiological abnormalities, including low-frequency activity, are common following TBI. Here, we investigate associative memory binding during PTA and test the hypothesis that misbinding is caused by pathological slowing of brain activity disrupting cortical communication. Thirty acute moderate to severe TBI patients (25 males; 5 females) and 26 healthy controls (20 males; 6 females) were tested with a precision working memory paradigm requiring the association of object and location information. Electrophysiological effects of TBI were assessed using resting-state EEG in a subsample of 17 patients and 21 controls. PTA patients showed abnormalities in working memory function and made significantly more misbinding errors than patients who were not in PTA and controls. The distribution of localization responses was abnormally biased by the locations of nontarget items for patients in PTA, suggesting a specific impairment of object and location binding. Slow-wave activity was increased following TBI. Increases in the δ-α ratio indicative of an increase in low-frequency power specifically correlated with binding impairment in working memory. Connectivity changes in TBI did not correlate with binding impairment. Working memory and electrophysiological abnormalities normalized at 6 month follow-up. These results show that patients in PTA show high rates of misbinding that are associated with a pathological shift toward lower-frequency oscillations.SIGNIFICANCE STATEMENT How do we remember what was where? The mechanism by which information (e.g., object and location) is integrated in working memory is a central question for cognitive neuroscience. Following significant head injury, many patients will experience a period of post-traumatic amnesia (PTA) during which this associative binding is disrupted. This may be because of electrophysiological changes in the brain. Using a precision working memory test and resting-state EEG, we show that PTA patients demonstrate impaired binding ability, and this is associated with a shift toward slower-frequency activity on EEG. Abnormal EEG connectivity was observed but was not specific to PTA or binding ability. These findings contribute to both our mechanistic understanding of working memory binding and PTA pathophysiology.

Abnormal dorsal attention network activation in memory impairment after traumatic brain injury.

Memory impairment is a common, disabling effect of traumatic brain injury. In healthy individuals, successful memory encoding is associated with activation of the dorsal attention network as well as suppression of the default mode network. Here, in traumatic brain injury patients we examined whether: (i) impairments in memory encoding are associated with abnormal brain activation in these networks; (ii) whether changes in this brain activity predict subsequent memory retrieval; and (iii) whether abnormal white matter integrity underpinning functional networks is associated with impaired subsequent memory. Thirty-five patients with moderate-severe traumatic brain injury aged 23-65 years (74% males) in the post-acute/chronic phase after injury and 16 healthy control subjects underwent functional MRI during performance of an abstract image memory encoding task. Diffusion tensor imaging was used to assess structural abnormalities across patient groups compared to 28 age-matched healthy controls. Successful memory encoding across all participants was associated with activation of the dorsal attention network, the ventral visual stream and medial temporal lobes. Decreased activation was seen in the default mode network. Patients with preserved episodic memory demonstrated increased activation in areas of the dorsal attention network. Patients with impaired memory showed increased left anterior prefrontal activity. White matter microstructure underpinning connectivity between core nodes of the encoding networks was significantly reduced in patients with memory impairment. Our results show for the first time that patients with impaired episodic memory show abnormal activation of key nodes within the dorsal attention network and regions regulating default mode network activity during encoding. Successful encoding was associated with an opposite direction of signal change between patients with and without memory impairment, suggesting that memory encoding mechanisms could be fundamentally altered in this population. We demonstrate a clear relationship between functional networks activated during encoding and underlying abnormalities within the structural connectome in patients with memory impairment. We suggest that encoding failures in this group are likely due to failed control of goal-directed attentional resources.

The neuron mixer and its impact on human brain dynamics.

A signal mixer facilitates rich computation, which has been the building block of modern telecommunication. This frequency mixing produces new signals at the sum and difference frequencies of input signals, enabling powerful operations such as heterodyning and multiplexing. Here, we report that a neuron is a signal mixer. We found through ex vivo and in vivo whole-cell measurements that neurons mix exogenous (controlled) and endogenous (spontaneous) subthreshold membrane potential oscillations, producing new oscillation frequencies, and that neural mixing originates in voltage-gated ion channels. Furthermore, we demonstrate that mixing is evident in human brain activity and is associated with cognitive functions. We found that the human electroencephalogram displays distinct clusters of local and inter-region mixing and that conversion of the salient posterior alpha-beta oscillations into gamma-band oscillations regulates visual attention. Signal mixing may enable individual neurons to sculpt the spectrum of neural circuit oscillations and utilize them for computational operations.

Population incidence and associated mortality of urinary tract infection in people living with dementia.

OBJECTIVES: Urinary tract infections (UTIs) frequently cause hospitalisation and death in people living with dementia (PLWD). We examine UTI incidence and associated mortality among PLWD relative to matched controls and people with diabetes and investigate whether delayed or withheld treatment further impacts mortality. METHODS: Data were extracted for n = 2,449,814 people aged ≥ 50 in Wales from 2000-2021, with groups matched by age, sex, and multimorbidity. Poisson regression was used to estimate incidences of UTI and mortality. Cox regression was used to study the effects of treatment timing. RESULTS: UTIs in dementia (HR=2.18, 95 %CI [1.88-2.53], p < .0) and diabetes (1.21[1.01-1.45], p = .035) were associated with high mortality, with the highest risk in individuals with diabetes and dementia (both) (2.83[2.40-3.34], p < .0) compared to matched individuals with neither dementia nor diabetes. 5.4 % of untreated PLWD died within 60 days of GP diagnosis-increasing to 5.9 % in PLWD with diabetes. CONCLUSIONS: Incidences of UTI and associated mortality are high in PLWD, especially in those with diabetes and dementia. Delayed treatment for UTI is further associated with high mortality.

Active elite rugby participation is associated with altered precentral cortical thickness.

There is growing concern that elite rugby participation may negatively influence brain health, but the underlying mechanisms are unclear. Cortical thickness is a widely applied biomarker of grey matter structure, but there is limited research into how it may be altered in active professional rugby players. Cross-sectional MRI data from 44 active elite rugby players, including 21 assessed within 1 week of head injury, and 47 healthy controls were analysed. We investigated how active elite rugby participation with and without sub-acute traumatic brain injury influenced grey matter structure using whole cortex and region of interest cortical thickness analyses. Relationships between cortical thickness and biomarkers of traumatic brain injury, including fractional anisotropy, plasma neurofilament light and glial fibrillary acidic protein, were also examined. In whole-cortex analyses, precentral cortical thickness in the right hemisphere was lower in rugby players compared with controls, which was due to reductions in non-injured players. Post hoc region of interest analyses showed non-injured rugby players had reduced cortical thickness in the inferior precentral sulcal thickness bilaterally (P = 0.005) and the left central sulcus (P = 0.037) relative to controls. In contrast, players in the sub-acute phase of mild traumatic brain injury had higher inferior precentral sulcal cortical thickness in the right hemisphere (P = 0.015). Plasma glial fibrillary acidic protein, a marker of astrocyte activation, was positively associated with right inferior precentral sulcal cortical thickness in injured rugby players (P = 0.0012). Elite rugby participation is associated with localized alterations in cortical thickness, specifically in sulcal motor regions. Sub-acute changes after mild traumatic brain injury are associated with evidence of astrocytic activation. The combination of cortical thickness and glial fibrillary acidic protein may be useful in understanding the pathophysiological relationship between sporting head injury and brain health.

Computerised cognitive assessment in patients with traumatic brain injury: an observational study of feasibility and sensitivity relative to established clinical scales.

Background: Online technology could potentially revolutionise how patients are cognitively assessed and monitored. However, it remains unclear whether assessments conducted remotely can match established pen-and-paper neuropsychological tests in terms of sensitivity and specificity. Methods: This observational study aimed to optimise an online cognitive assessment for use in traumatic brain injury (TBI) clinics. The tertiary referral clinic in which this tool has been clinically implemented typically sees patients a minimum of 6 months post-injury in the chronic phase. Between March and August 2019, we conducted a cross-group, cross-device and factor analyses at the St. Mary's Hospital TBI clinic and major trauma wards at Imperial College NHS trust and St. George's Hospital in London (UK), to identify a battery of tasks that assess aspects of cognition affected by TBI. Between September 2019 and February 2020, we evaluated the online battery against standard face-to-face neuropsychological tests at the Imperial College London research centre. Canonical Correlation Analysis (CCA) determined the shared variance between the online battery and standard neuropsychological tests. Finally, between October 2020 and December 2021, the tests were integrated into a framework that automatically generates a results report where patients' performance is compared to a large normative dataset. We piloted this as a practical tool to be used under supervised and unsupervised conditions at the St. Mary's Hospital TBI clinic in London (UK). Findings: The online assessment discriminated processing-speed, visual-attention, working-memory, and executive-function deficits in TBI. CCA identified two significant modes indicating shared variance with standard neuropsychological tests (r = 0.86, p < 0.001 and r = 0.81, p = 0.02). Sensitivity to cognitive deficits after TBI was evident in the TBI clinic setting under supervised and unsupervised conditions (F (15,555) = 3.99; p < 0.001). Interpretation: Online cognitive assessment of TBI patients is feasible, sensitive, and efficient. When combined with normative sociodemographic models and autogenerated reports, it has the potential to transform cognitive assessment in the healthcare setting. Funding: This work was funded by a National Institute for Health Research (NIHR) Invention for Innovation (i4i) grant awarded to DJS and AH (II-LB-0715-20006).

Traumatic brain injury: a comparison of diffusion and volumetric magnetic resonance imaging measures.

Cognitive impairment after traumatic brain injury remains hard to predict. This is partly because axonal injury, which is of fundamental importance, is difficult to measure clinically. Advances in MRI allow axonal injury to be detected after traumatic brain injury, but the most sensitive approach is unclear. Here, we compare the performance of diffusion tensor imaging, neurite orientation dispersion and density-imaging and volumetric measures of brain atrophy in the identification of white-matter abnormalities after traumatic brain injury. Thirty patients with moderate-severe traumatic brain injury in the chronic phase and 20 age-matched controls had T1-weighted and diffusion MRI. Neuropsychological tests of processing speed, executive functioning and memory were used to detect cognitive impairment. Extensive abnormalities in neurite density index and orientation dispersion index were observed, with distinct spatial patterns. Fractional anisotropy and mean diffusivity also indicated widespread abnormalities of white-matter structure. Neurite density index was significantly correlated with processing speed. Slower processing speed was also related to higher mean diffusivity in the corticospinal tracts. Lower white-matter volumes were seen after brain injury with greater effect sizes compared to diffusion metrics; however, volume was not sensitive to changes in cognitive performance. Volume was the most sensitive at detecting change between groups but was not specific for determining relationships with cognition. Abnormalities in fractional anisotropy and mean diffusivity were the most sensitive diffusion measures; however, neurite density index and orientation dispersion index may be more spatially specific. Lower neurite density index may be a useful metric for examining slower processing speed.

Axonal marker neurofilament light predicts long-term outcomes and progressive neurodegeneration after traumatic brain injury.

Axonal injury is a key determinant of long-term outcomes after traumatic brain injury (TBI) but has been difficult to measure clinically. Fluid biomarker assays can now sensitively quantify neuronal proteins in blood. Axonal components such as neurofilament light (NfL) potentially provide a diagnostic measure of injury. In the multicenter BIO-AX-TBI study of moderate-severe TBI, we investigated relationships between fluid biomarkers, advanced neuroimaging, and clinical outcomes. Cerebral microdialysis was used to assess biomarker concentrations in brain extracellular fluid aligned with plasma measurement. An experimental injury model was used to validate biomarkers against histopathology. Plasma NfL increased after TBI, peaking at 10 days to 6 weeks but remaining abnormal at 1 year. Concentrations were around 10 times higher early after TBI than in controls (patients with extracranial injuries). NfL concentrations correlated with diffusion MRI measures of axonal injury and predicted white matter neurodegeneration. Plasma TAU predicted early gray matter atrophy. NfL was the strongest predictor of functional outcomes at 1 year. Cerebral microdialysis showed that NfL concentrations in plasma and brain extracellular fluid were highly correlated. An experimental injury model confirmed a dose-response relationship of histopathologically defined axonal injury to plasma NfL. In conclusion, plasma NfL provides a sensitive and clinically meaningful measure of axonal injury produced by TBI. This reflects the extent of underlying damage, validated using advanced MRI, cerebral microdialysis, and an experimental model. The results support the incorporation of NfL sampling subacutely after injury into clinical practice to assist with the diagnosis of axonal injury and to improve prognostication.

Genome-wide discovered psychosis-risk gene ZNF804A impacts on white matter microstructure in health, schizophrenia and bipolar disorder.

Background. Schizophrenia (SZ) and bipolar disorder (BD) have both been associated with reduced microstructural white matter integrity using, as a proxy, fractional anisotropy (FA) detected using diffusion tensor imaging (DTI). Genetic susceptibility for both illnesses has also been positively correlated in recent genome-wide association studies with allele A (adenine) of single nucleotide polymorphism (SNP) rs1344706 of the ZNF804A gene. However, little is known about how the genomic linkage disequilibrium region tagged by this SNP impacts on the brain to increase risk for psychosis. This study aimed to assess the impact of this risk variant on FA in patients with SZ, in those with BD and in healthy controls. Methods. 230 individuals were genotyped for the rs1344706 SNP and underwent DTI. We used tract-based spatial statistics (TBSS) followed by an analysis of variance, with threshold-free cluster enhancement (TFCE), to assess underlying effects of genotype, diagnosis and their interaction, on FA. Results. As predicted, statistically significant reductions in FA across a widely distributed brain network (p < 0.05, TFCE-corrected) were positively associated both with a diagnosis of SZ or BD and with the double (homozygous) presence of the ZNF804A rs1344706 risk variant (A). The main effect of genotype was medium (d = 0.48 in a 44,054-voxel cluster) and the effect in the SZ group alone was large (d = 1.01 in a 51,260-voxel cluster), with no significant effects in BD or controls, in isolation. No areas under a significant diagnosis by genotype interaction were found. Discussion. We provide the first evidence in a predominantly Caucasian clinical sample, of an association between ZNF804A rs1344706 A-homozygosity and reduced FA, both irrespective of diagnosis and particularly in SZ (in overlapping brain areas). This suggests that the previously observed involvement of this genomic region in psychosis susceptibility, and in impaired functional connectivity, may be conferred through it inducing abnormalities in white matter microstructure.