Investigating cognitive reserve, symptom resolution and brain connectivity in mild traumatic brain injury.

BACKGROUND: A proportion of patients with mild traumatic brain injury (mTBI) suffer long-term consequences, and the reasons behind this are still poorly understood. One factor that may affect outcomes is cognitive reserve, which is the brain's ability to maintain cognitive function despite injury. It is often assessed through educational level or premorbid IQ tests. This study aimed to explore whether there were differences in post-concussion symptoms and symptom resolution between patients with mTBI and minor orthopedic injuries one week and three months after injury. Additional aims were to explore the relationship between cognitive reserve and outcome, as well as functional connectivity according to resting state functional magnetic resonance imaging (rs-fMRI). METHOD: Fifteen patients with mTBI and 15 controls with minor orthopedic injuries were recruited from the emergency department. Assessments, including Rivermead Post-Concussion Questionnaire (RPQ), neuropsychological testing, and rs-fMRI scans, were conducted on average 7 days (SD = 2) and 122 days (SD = 51) after injury. RESULTS: At the first time point, significantly higher rates of post-concussion symptoms (U = 40.0, p = 0.003), state fatigue (U = 56.5, p = 0.014), and fatigability (U = 58.5, p = 0.025) were observed among the mTBI group than among the controls. However, after three months, only the difference in post-concussion symptoms remained significant (U = 27.0, p = 0.003). Improvement in post-concussion symptoms was found to be significantly correlated with cognitive reserve, but only in the mTBI group (Spearman's rho = -0.579, p = .038). Differences in the trajectory of recovery were also observed for fatigability between the two groups (U = 36.5, p = 0.015). Moreover, functional connectivity differences in the frontoparietal network were observed between the groups, and for mTBI patients, functional connectivity differences in an executive control network were observed over time. CONCLUSION: The findings of this pilot study suggest that mTBI, compared to minor orthopedic trauma, is associated to both functional connectivity changes in the brain and concussion-related symptoms. While there is improvement in these symptoms over time, a small subgroup with lower cognitive reserve appears to experience more persistent and possibly worsening symptoms over time. This, however, needs to be validated in larger studies. TRIAL REGISTRATION: NCT05593172. Retrospectively registered.

White matter abnormalities mediate the association between masticatory dysfunction and cognition among older adults.

BACKGROUND: Masticatory parameters, such as reduced number of teeth and posterior contacts, have been shown to be associated with reduced cognitive status. The underlying mechanisms that affect these associations, are however, not well understood. OBJECTIVES: The study aims to investigate the association between masticatory dysfunction and cognition and explore the mediating effect of brain structure. METHODS: In this cross-sectional study, 45 older adults with subjective masticatory dysfunction (mean age 72.3 ± 4.0 years) were included. Mini-Mental State Examination score <25, brain trauma, neurological disease, neurodegenerative disorders, depression or poor Swedish language skills were criteria for exclusion. Cognitive functions (executive function and episodic memory) and masticatory dysfunction defined by functional occluding status (FOS; the number of occluding units and number of remaining teeth) were analysed with partial correlation models. Structural magnetic resonance imaging was performed on 28 feasible participants. Multiple regression analyses were performed to evaluate the predictive value of brain structure and white matter hypointensities (WM-hypo) on cognitive functions. A mediation analysis was applied to assess significant predictor/s of the association between FOS and cognition. RESULTS: Both episodic memory and executive functions were positively correlated with FOS. WM-hypo predicted cognitive status (executive function, p ≤ .01). WM-hypo mediated 66.6% (p = 0.06) of the association between FOS and executive functions. CONCLUSION: Associations between FOS and cognitive functions are reported, where FOS, a potential modifiable risk factor, was related to both episodic memory and executive functions. The mediating effect of WM-hypo on the association between FOS and executive functions highlights the impact of the vascularisation of the brain on the link between mastication and cognition. The present study provides increased knowledge that bridges the gap between masticatory dysfunction and cognition.

Cognitive and mental fatigue in chronic pain: cognitive functions, emotional aspects, biomarkers and neuronal correlates-protocol for a descriptive cross-sectional study.

INTRODUCTION: Chronic pain (CP) is one of the most frequently presenting conditions in health care and many patients with CP report mental fatigue and a decline in cognitive functioning. However, the underlying mechanisms are still unknown. METHODS AND ANALYSIS: This study protocol describes a cross-sectional study aimed at investigating the presence of self-rated mental fatigue, objectively measured cognitive fatigability and executive functions and their relation to other cognitive functions, inflammatory biomarkers and brain connectivity in patients with CP. We will control for pain-related factors such as pain intensity and secondary factors such as sleep disturbances and psychological well-being. Two hundred patients 18-50 years with CP will be recruited for a neuropsychological investigation at two outpatient study centres in Sweden. The patients are compared with 36 healthy controls. Of these, 36 patients and 36 controls will undergo blood sampling for inflammatory markers, and of these, 24 female patients and 22 female controls, between 18 and 45 years, will undergo an functional MRI investigation. Primary outcomes are cognitive fatigability, executive inhibition, imaging and inflammatory markers. Secondary outcomes include self-rated fatigue, verbal fluency and working memory. The study provides an approach to study fatigue and cognitive functions in CP with objective measurements and may demonstrate new models of fatigue and cognition in CP. ETHICS AND DISSEMINATION: The study has been approved by the Swedish Ethics Review Board (Dnr 2018/424-31; 2018/1235-32; 2018/2395-32; 2019-66148; 2022-02838-02). All patients gave written informed consent to participate in the study. The study findings will be disseminated through publications in journals within the fields of pain, neuropsychology and rehabilitation. Results will be spread at relevant national and international conferences, meetings and expert forums. The results will be shared with user organisations and their members as well as relevant policymakers. TRIAL REGISTRATION NUMBER: NCT05452915.

Seeing Beyond Your Nose? The Effects of Lifelong Olfactory Sensory Deprivation on Cerebral Audio-visual Integration.

Lifelong auditory and visual sensory deprivation have been demonstrated to alter both perceptual acuity and the neural processing of remaining senses. Recently, it was demonstrated that individuals with anosmia, i.e. complete olfactory sensory deprivation, displayed enhanced multisensory integration performance. Whether this ability is due to a reorganization of olfactory processing regions to focus on cross-modal multisensory information or whether it is due to enhanced processing within multisensory integration regions is not known. To dissociate these two outcomes, we investigated the neural processing of dynamic audio-visual stimuli in individuals with congenital anosmia and matched controls (both groups, n = 33) using functional magnetic resonance imaging. Specifically, we assessed whether the previously demonstrated multisensory enhancement is related to cross-modal processing of multisensory stimuli in olfactory associated regions, the piriform and olfactory orbitofrontal cortices, or enhanced multisensory processing in established multisensory integration regions, the superior temporal and intraparietal sulci. No significant group differences were found in the a priori hypothesized regions using region of interest analyses. However, exploratory whole-brain analysis suggested higher activation related to multisensory integration within the posterior superior temporal sulcus, in close proximity to the multisensory region of interest, in individuals with congenital anosmia. No group differences were demonstrated in olfactory associated regions. Although results were outside our hypothesized regions, combined, they tentatively suggest that enhanced processing of audio-visual stimuli in individuals with congenital anosmia may be mediated by multisensory, and not primary sensory, cerebral regions.

Cognitive changes and neural correlates after oral rehabilitation procedures in older adults: a protocol for an interventional study.

BACKGROUND: Epidemiological studies show an association between masticatory function and cognitive impairment. This has further strengthened the notion that tooth loss and impaired masticatory function may be risk factors for dementia and cognitive decline. Animal experiments have indicated a causal relationship and several possible mechanisms have been discussed. This evidence is, however, lacking in humans. Therefore, in the current interventional study, we aim to investigate the effect of rehabilitation of masticatory function on cognition in older adults. METHODS: Eighty patients indicated for prosthodontic rehabilitation will be randomly assigned to an experimental or a control group. Participants will conduct neuropsychological assessments, masticatory performance tests, saliva tests, optional magnetic resonance imaging, and answer questionnaires on oral health impact profiles and hospital anxiety and depression scale before, 3 months, and 1 year after oral rehabilitation. The difference between the two groups is that the control group will be tested an additional time, (at an interval of about 3 months) before the onset of the oral rehabilitation procedure. The primary outcome is a change in measures of episodic memory performance. DISCUSSION: Although tooth loss and masticatory function are widespread in older people, it is still an underexplored modifiable risk factor potentially contributing to the development of cognitive impairment. If rehabilitation of masticatory function shows positive effects on the neurocognitive function, this will have great implications on future health care for patients with impaired masticatory status. The present project may provide a new avenue for the prevention of cognitive decline in older individuals. TRIAL REGISTRATION: The protocol for the study was retrospectively registered in ClinicalTrials.gov Identifier: NCT04458207, dated 02-07-2020.

Normal Olfactory Functional Connectivity Despite Lifelong Absence of Olfactory Experiences.

Congenital blindness is associated with atypical morphology and functional connectivity within and from visual cortical regions; changes that are hypothesized to originate from a lifelong absence of visual input and could be regarded as a general (re) organization principle of sensory cortices. Challenging this is the fact that individuals with congenital anosmia (lifelong olfactory sensory loss) display little to no morphological changes in the primary olfactory cortex. To determine whether olfactory input from birth is essential to establish and maintain normal functional connectivity in olfactory processing regions, akin to the visual system, we assessed differences in functional connectivity within the olfactory cortex between individuals with congenital anosmia (n = 33) and matched controls (n = 33). Specifically, we assessed differences in connectivity between core olfactory processing regions as well as differences in regional homogeneity and homotopic connectivity within the primary olfactory cortex. In contrast to congenital blindness, none of the analyses indicated atypical connectivity in individuals with congenital anosmia. In fact, post-hoc Bayesian analysis provided support for an absence of group differences. These results suggest that a lifelong absence of olfactory experience has a limited impact on the functional connectivity in the olfactory cortex, a finding that indicates a clear difference between sensory modalities in how sensory cortical regions develop.

Phenotypic variability in chorea-acanthocytosis associated with novel VPS13A mutations.

OBJECTIVE: To perform a comprehensive characterization of a cohort of patients with chorea-acanthocytosis (ChAc) in Sweden. METHODS: Clinical assessments, targeted genetic studies, neuroimaging with MRI, [18F]-fluorodeoxyglucose (FDG) PET, and dopamine transporter with 123I FP-CIT (DaTscan) SPECT. One patient underwent magnetic resonance spectroscopy (MRS). RESULTS: Four patients living in Sweden but with different ethnical backgrounds were included. Their clinical features were variable. Biallelic VPS13A mutations were confirmed in all patients, including 3 novel mutations. All tested patients had either low or absent chorein levels. One patient had progressive caudate atrophy. Investigation using FDG-PET revealed severe bilateral striatal hypometabolism, and DaTscan SPECT displayed presynaptic dopaminergic deficiency in 3 patients. MRS demonstrated reduced N-acetylaspartate/creatine (Cr) ratio and mild elevation of both choline/Cr and combined glutamate and glutamine/Cr in the striatum in 1 case. One patient died during sleep, and another was treated with deep brain stimulation, which transiently attenuated feeding dystonia but not his gait disorder or chorea. CONCLUSIONS: Larger longitudinal neuroimaging studies with different modalities, particularly MRS, are needed to determine their potential role as biomarkers for ChAc.

Morphological changes in secondary, but not primary, sensory cortex in individuals with life-long olfactory sensory deprivation.

Individuals with congenital sensory deprivation usually demonstrate altered brain morphology in areas associated with early processing of the absent sense. Here, we aimed to establish whether this also applies to individuals born without a sense of smell (congenital anosmia) by comparing cerebral morphology between 33 individuals with isolated congenital anosmia and matched controls. We detected no morphological alterations in the primary olfactory (piriform) cortex. However, individuals with anosmia demonstrated gray matter volume atrophy in bilateral olfactory sulci, explained by decreased cortical area, curvature, and sulcus depth. They further demonstrated increased gray matter volume and cortical thickness in the medial orbital gyri; regions closely associated with olfactory processing, sensory integration, and value-coding. Our results suggest that a lifelong absence of sensory input does not necessarily lead to morphological alterations in primary sensory cortex and extend previous findings with divergent morphological alterations in bilateral orbitofrontal cortex, indicating influences of different developmental processes.

Fatigue and Cognitive Fatigability in Mild Traumatic Brain Injury are Correlated with Altered Neural Activity during Vigilance Test Performance.

INTRODUCTION: Fatigue is the most frequently reported persistent symptom following a mild traumatic brain injury (mTBI), but the explanations for the persisting fatigue symptoms in mTBI remain controversial. In this study, we investigated the change of cerebral blood flow during the performance of a psychomotor vigilance task (PVT) by using pseudo-continuous arterial spin labeling (PCASL) MRI technique to better understand the relationship between fatigability and brain activity in mTBI. MATERIAL AND METHODS: Ten patients (mean age: 37.5 ± 11.2 years) with persistent complaints of fatigue after mTBI and 10 healthy controls (mean age 36.9 ± 11.0 years) were studied. Both groups completed a 20-min long PVT inside a clinical MRI scanner during simultaneous measurements of reaction time and regional cerebral blood flow (rCBF) with PCASL technique. Cognitive fatigability and neural activity during PVT were analyzed by dividing the performance and rCBF data into quintiles in addition to the assessment of self-rated fatigue before and after the PVT. RESULTS: The patients showed significant fatigability during the PVT while the controls had a stable performance. The variability in performance was also significantly higher among the patients, indicating monitoring difficulty. A three-way ANOVA, modeling of the rCBF data demonstrated that there was a significant interaction effect between the subject group and performance time during PVT in a mainly frontal/thalamic network, indicating that the pattern of rCBF change for the mTBI patients differed significantly from that of healthy controls. In the mTBI patients, fatigability at the end of the PVT was related to increased rCBF in the right middle frontal gyrus, while self-rated fatigue was related to increased rCBF in left medial frontal and anterior cingulate gyri and decreases of rCBF in a frontal/thalamic network during this period. DISCUSSION: This study demonstrates that PCASL is a useful technique to investigate neural correlates of fatigability and fatigue in mTBI patients. Patients suffering from fatigue after mTBI used different brain networks compared to healthy controls during a vigilance task and in mTBI, there was a distinction between rCBF changes related to fatigability vs. perceived fatigue. Whether networks for fatigability and self-rated fatigue are different, needs to be investigated in future studies.

Post mTBI fatigue is associated with abnormal brain functional connectivity.

This study set out to investigate the behavioral correlates of changes in resting-state functional connectivity before and after performing a 20 minute continuous psychomotor vigilance task (PVT) for patients with chronic post-concussion syndrome. Ten patients in chronic phase after mild traumatic brain injury (mTBI) with persisting symptoms of fatigue and ten matched healthy controls participated in the study. We assessed the participants' fatigue levels and conducted resting-state fMRI before and after a sustained PVT. We evaluated the changes in brain functional connectivity indices in relation to the subject's fatigue behavior using a quantitative data-driven analysis approach. We found that the PVT invoked significant mental fatigue and specific functional connectivity changes in mTBI patients. Furthermore, we found a significant linear correlation between self-reported fatigue and functional connectivity in the thalamus and middle frontal cortex. Our findings indicate that resting-state fMRI measurements may be a useful indicator of performance potential and a marker of fatigue level in the neural attentional system.

Shape analysis of the corpus callosum in Alzheimer's disease and frontotemporal lobar degeneration subtypes.

Morphology of the corpus callosum is a useful biomarker of neuronal loss, as different patterns of cortical atrophy help to distinguish between dementias such as Alzheimer's disease (AD) and frontotemporal lobar degeneration (FTLD). We used a sophisticated morphometric analysis of the corpus callosum in FTLD subtypes including frontotemporal dementia (FTD), semantic dementia (SD), and progressive non-fluent aphasia (PNFA), and compared them to AD patients and 27 matched controls. FTLD patient subgroups diverged in their callosal morphology profiles, with FTD patients showing marked widespread differences, PNFA patients with differences largely in the anterior half of the callosum, and SD patients differences in a small segment of the genu. AD patients showed differences in predominantly posterior callosal regions. This study is consistent with our previous findings showing significant cortical and subcortical regional atrophy across FTLD subtypes, and suggests that callosal atrophy patterns differentiate AD from FTLD, and FTLD subtypes.

Cortical responses to amphetamine exposure studied by pCASL MRI and pharmacokinetic/pharmacodynamic dose modeling.

INTRODUCTION: Perfusion measurement by arterial spin labeling (ASL) techniques is well suited for pharmaceutical magnetic resonance imaging (phMRI) studies to investigate how drugs change the cerebral perfusion status and further, neuronal activity. MATERIALS AND METHOD: Twelve healthy normal male volunteers participated in the study which was based on a double blinded design. Six subjects were randomly selected to receive a single oral dose of 20mg d-amphetamine and six were given placebo. Perfusion measurements by pseudo-continuous ASL (pCASL) technique were repeatedly performed at 10 different time points with a 3T clinical MRI scanner during a 10 hour period after dose together with physiologic data and blood sample collections. The dynamic changes in cerebral perfusion in response to the plasma concentration variations of d-amphetamine were analyzed at voxel-level and for regions of interest. RESULTS: Compared to the placebo group a 20% reduction in cerebral blood flow (CBF) was observed in gray matter for the subjects that received d-amphetamine. The most significant reduction of regional CBF (rCBF) was detected in the basal ganglia, frontal region and insular cortex using voxel based analysis. A relation between d-amphetamine exposure and CBF response was found using PK/PD modeling, which predicted on average a 15% decrease of the CBF in gray matter at a plasma concentration of 30 ng/ml. CONCLUSION: In this study we have demonstrated that repeated perfusion measurements by pCASL technique was sufficiently robust to differentiate the neurological response between the groups that received d-amphetamine and placebo. Quantitative and repetitive CBF measurements can be used for PK/PD modeling of CNS drug responses in humans.