Temporally Graded Activation of Neocortical Regions in Response to Memories of Different Ages

The temporally graded memory impairment seen in many neurobehavioral disorders implies different neuroanatomical pathways and/or cognitive mechanisms involved in storage and retrieval of memories of different ages. A dynamic interaction between medial-temporal and neocortical brain regions has been proposed to account for memory\u27s greater permanence with time. Despite considerable debate concerning its time-dependent role in memory retrieval, medial-temporal lobe activity has been well studied. However, the relative participation of neocortical regions in recent and remote memory retrieval has received much less attention. Using functional magnetic resonance imaging, we demonstrate robust, temporally graded signal differences in posterior cingulate, right middle frontal, right fusiform, and left middle temporal regions in healthy older adults during famous name identification from two disparate time epochs. Importantly, no neocortical regions demonstrated greater response to older than to recent stimuli. Our results suggest a possible role of these neocortical regions in temporally dating items in memory and in establishing and maintaining memory traces throughout the lifespan. Theoretical implications of these findings for the two dominant models of remote memory functioning (Consolidation Theory and Multiple Trace Theory) are discussed

EXPLAINING LATERALITY

Working with multi-species allometric relations and drawing on mammalian theorist Denenberg’s works, I provide an explanatory theory of the mammalian dual-brain as no prior account has

Cigarette smoking is associated with cortical thinning in anterior frontal regions, insula and regions showing atrophy in early Alzheimer’s Disease

Background Magnetic resonance imaging studies of cigarette smoking-related effects on human brain structure primarily focused on cortical volumes. Much less is known about the effects of smoking on cortical thickness. Smokers and Non-smokers were compared on regional cortical thickness. We predicted smokers would demonstrate greater age-related thinning localized to anterior frontal regions that serve as nodes for the executive, salience, and emotional regulation networks (ESER regions) and those demonstrating significant atrophy in early Alzheimer’s Disease (AD regions). Methods Non-smokers (n = 41) and smokers (n = 41), 22–70 years of age, completed a 4 T MRI study. Regional cortical thickness was quantitated via FreeSurfer. In smokers, associations between smoking severity, decision-making, impulsivity, and regional cortical thickness were examined. Results Smokers demonstrated cortical thinning in the medial and lateral OFC, insula, entorhinal, fusiform, middle temporal, and Composite AD regions. In Smokers, greater pack-years were associated with thinner lateral OFC, middle temporal, inferior parietal, fusiform, precuneus, and Composite AD regions. In Smokers, poorer decision-making/greater risk taking was related to thinner cortices in caudal ACC, rostral middle frontal and superior frontal gyri, and Composite ESER. Higher self-reported impulsivity was associated with thinner rostral and caudal ACC. Conclusions This study provides additional evidence that cigarette smoking is associated with thinner cortices in regions implicated in the development and maintenance of substance use disorders and in regions demonstrating significant atrophy in early AD. The novel structure-function relationships in Smokers further our understanding of the neurobiological substrates potentially underlying the neuropsychological abnormalities documented in smokers

Neuroanatomical Variability of Religiosity

We hypothesized that religiosity, a set of traits variably expressed in the population, is modulated by neuroanatomical variability. We tested this idea by determining whether aspects of religiosity were predicted by variability in regional cortical volume. We performed structural magnetic resonance imaging of the brain in 40 healthy adult participants who reported different degrees and patterns of religiosity on a survey. We identified four Principal Components of religiosity by Factor Analysis of the survey items and associated them with regional cortical volumes measured by voxel-based morphometry. Experiencing an intimate relationship with God and engaging in religious behavior was associated with increased volume of R middle temporal cortex, BA 21. Experiencing fear of God was associated with decreased volume of L precuneus and L orbitofrontal cortex BA 11. A cluster of traits related with pragmatism and doubting God's existence was associated with increased volume of the R precuneus. Variability in religiosity of upbringing was not associated with variability in cortical volume of any region. Therefore, key aspects of religiosity are associated with cortical volume differences. This conclusion complements our prior functional neuroimaging findings in elucidating the proximate causes of religion in the brain

Advanced clinical MRI for better outcome in epilepsy surgery. Focusing on fMRI and prediction of verbal memory decline.

Abstract Aim: The aim of the thesis was to evaluate the use of advanced MRI technology to improve results of epilepsy surgery, with focus on language and memory functions. Methods: In paper I, 25 patients with drug-resistant epilepsy were retrospectively included in the study for having been referred to high resolution 3T MRI with and without surface coils. The surface coils were placed over the suspected epileptogenic zone. The efficacy of the coils was assessed and graded in relation to their placement. In papers II, III and IV, a functional MRI (fMRI) paradigm, including both a verbal encoding task and a visuospatial task, was designed and implemented. The medial temporal lobe (MTL) for memory and the anterior language area were studied. In paper III, a standard word generation fMRI paradigm was also included. In these three studies, the test was performed in 15 healthy right handed subjects (paper II), 6 patients with drug-resistant temporal lobe epilepsy (TLE) with mixed handedness and 10 controls (paper III) and 14 TLE patients eligible for resective surgery (paper IV), respectively. A bootstrap algorithm was used to calculate lateralization indices (LI) and LI-curves. In paper IV, a clinical risk assessment score was created from collected clinical data. Additional value from fMRI LI was correlated to post-surgical memory decline. Results: Surface coil 3T MRI did not contribute to detection of previously undiagnosed lesions. In 20% of patients, 3T MRI, compared with previous 1.0-1.5T MRI, provided new information about cortical lesions. The fMRI paradigm visualized memory-related activity in the MTL and provided information regarding language processes. LI and LI-curves for memory at group level were consistent with previous studies, but a variety of activation effects were found at the individual level. LI-curves added complementary information for individual subjects with uncharacteristic results. The verbal encoding task provided information on verbal memory, which had equal lateralization as language in right-handed subjects, but not always in left-handed subjects and TLE patients. Bilateral fMRI language representation was seen in 2 right TLE patients who later suffered verbal memory decline post-operatively. Conclusion: High resolution 3T MRI is valuable for lesion detection, but surface coils do not provide further crucial information. The fMRI paradigm activates memory and language areas that can be studied at an individual level using LIcurves. Analysis of language patterns seems to be important for prediction of memory outcome in both left and right TLE. fMRI indices may identify an unexpected high risk for post-operative verbal memory decline in right TLE patients

Investigating the Relationship Between Vascular Health, Gait, and Cognition in Community-Dwelling Older Adults Without Dementia

Cardiovascular disease (CVD) risk factors contribute to neuropathological changes within regions of the brain that are involved with both cognitive and motor control processes, and have been identified as potentially modifiable dementia and gait dysfunction risk factors. Exercise training is a corner-stone treatment for vascular risk factor control, and evidence suggests that physical and cognitive training can benefit cognition and gait; however, the exercise training modality that can provide the greatest cognitive benefit remains elusive. Therefore, the purpose of this thesis was three-fold: (i) to determine whether CVD risk factors and gait were associated with cognitive functioning, (ii) to determine whether blood pressure dipping status was associated with cognitive and gait impairments in community-dwelling older adults, and iii) to examine the impact of a dual-task gait training and aerobic exercise (DAE) on cognition, gait, and vascular health. Cumulative CVD risk was an independent predictor of executive functioning. Cross-sectional differences in cognition and usual and dual-task gait were observed between older adults with preserved blood pressure dipping and non-dippers. Last, 26-weeks of DAE training improved cognition and usual and dual-task gait, and the improvements in cognition were maintained for at least 6 months after the exercise program. The management of traditional and novel CVD risk factors should be a primary aim of prevention strategies aimed at mitigating cognitive decline. Although DAE training can benefit cognition and gait, further work is required to unequivocally determine the efficacy of DAE training as a method to improve brain health in older adults without dementia

Mental stimulation and multimodal trials to prevent cognitive impairment and Alzheimer ́s disease

Theoretical models of dynamic biomarkers underlying the development of Alzheimer´s Disease (AD) acknowledge that there is inter-individual variability in the cognitive performance associated with any level of AD pathology. Mentally stimulating activities such as schooling, occupation, and leisure activities, may contribute to this variability, but it is yet unclear how this can be best assessed, and how such effects can vary across AD severity and among individuals at-risk for cognitive impairment. The association between mental stimulation and cognitive performance also suggests that it is important to account for mental stimulation levels in randomized clinical trials (RCTs) comparing rates of cognitive change between interventions (i.e., drugs, lifestyle interventions) and controls. The aim of this thesis was to investigate a) how pre-existing levels of occupational complexity affect the cognitive outcomes of a multimodal lifestyle-based RCT among older adults at increased risk for dementia based on a validated risk score b) if occupational complexity is associated to cognitive performance among individuals at-risk for dementia, including individuals in the early stages of symptomatic AD (prodromal AD) and c) if occupational complexity is associated with resilience to AD pathology, measured with validated biomarkers and neuroimaging among individuals at-risk for cognitive impairment and with prodromal AD. The four studies in this thesis were based on data from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER), the Karolinska University Hospital electronic database and biobank for clinical research (GEDOC) and The Multimodal Prevention Trial for Alzheimer´s Disease (MIND-ADmini). Study I. This study used data from the FINGER study (N=1026) to investigate if preexisting levels of occupational complexity were associated with cognitive function at baseline, and if occupational complexity was associated with the rate of change in cognition during the 2-year intervention period. For all measures of occupational complexity, higher levels of complexity were associated with better cognitive outcomes at baseline. Occupational complexity was not associated with the rate of cognitive change during the intervention, except for the executive function outcome, for which higher levels of complexity with data predicted increased improvement ((ß[SE]: .028[.014], p=.044). Study II. This study used data from the FINGER neuroimaging cohort, to investigate if the association between occupational complexity and cognition was moderated by measures of brain integrity, both in terms of magnetic resonance imaging (MRI, N=126) and Pittsburgh-B Compound – Positron Emission Tomography (PiB-PET, N=41). The results showed that higher levels of occupational complexity were associated with better cognitive performance for some outcomes after adjusting for Alzheimer’s Disease Signature (ADS) and medial temporal atrophy (MTA). However, for most types of neuropathology and cognitive outcomes, moderation effects indicated that higher occupational complexity levels were associated with better cognitive performance only in people with higher brain integrity, suggesting lack of occupational complexity-related resilience mechanisms. Study III. This study investigated the association between mental stimulation (occupational complexity and education) and validated AD biomarkers, Aβ1–42, p-tau and t-tau measured in cerebrospinal fluid (CSF). Using data from the GEDOC database, 174 individuals with prodromal AD were included, and analyses were adjusted for cognitive function. The results indicated that both higher occupational complexity and education were associated with higher levels of p-tau and t-tau. For education the association with tau pathology was age dependent. No association was found with Aβ1– 42. This suggests that higher education and occupational complexity may provide resilience against tau-related pathology in prodromal AD. Study IV. This study used data from FINGER, GEDOC, and MIND-ADmini, thus including a total of 1410 individuals, 1207 at-risk for dementia and 203 with Prodromal AD. The aim was to to compare the two most common rating systems for occupational complexity, the Occupation Information Network (O*NET) and the Dictionary of Occupational Titles (DOT) and assess if there was an association between occupational complexity and episodic memory performance among individuals at-risk for dementia. The study found that higher occupational complexity was only associated with memory performance in the FINGER cohort but not the two prodromal AD cohorts. The correlation between the two rating systems was moderate to strong, and highly significant (Spearman’s rho = 0.5-0.6, p <.001). Conclusions. Higher levels of Occupational complexity are associated with better cognitive performance among older individuals at-risk for dementia (and with no substantial cognitive impairment), but does not affect the intervention effect in the FINGER multidomain lifestyle-based RCT, apart from the effect on executive function. Occupational complexity does not seem to provide strong resilience against neuropathology among individuals at-risk for cognitive impairment. Among individuals with prodromal AD, higher levels of occupational complexity do seem to provide resilience to tau-related pathology measured with CSF markers but is not associated with better episodic memory performance. Measuring occupational complexity with the DOT or O*NET system seems to yield similar results, as the two systems scores are correlated

Cardiorespiratory fitness and virtual navigation in healthy older adults

One of the earliest symptoms of Alzheimer’s disease (AD) and age-related cognitive decline is topographical disorientation or impairment to spatial navigation. Furthermore, aging and AD are associated with cortical gray-matter thinning, particularly in the medial temporal and posterior cingulate regions, which have been associated with spatial navigation. Aerobic exercise has been well-established as a beneficial intervention to curtail the neurodegenerative effects of aging. This study aims to explore the relationship between cardiorespiratory fitness (CRF), and two markers of AD and cognitive aging, virtual navigation ability and cortical thickness of the entorhinal, parahippocampal and retrosplenial regions. Cross-sectional data utilized in this study was collected from 23 healthy older adults (60-80 years). Measures included in our analyses consisted of estimated VO2max, T1-weighted structural MR images, and behavioral performance on a virtual navigation task, measured as numbers of objects located during recall. Cortical thickness of the regions of interest (ROIs) was determined by processing T1-weighted MR images in FreeSurfer. We hypothesized that greater CRF would correlate with improved virtual navigation performance and greater cortical thickness of ROIs. Our analyses did not reveal statistically significant relationships between CRF and navigation performance or CRF and cortical thickness. However, Pearson’s correlations found right retrosplenial cortical (RSC) thickness and navigation performance to be significantly related. Multiple regression models of right RSC thickness and navigation performance were performed controlling for age, sex, education and task version. These analyses revealed that greater right RSC thickness predicted navigation performance. Additionally, this model showed that older age predicts decline in navigation performance. Our findings did not survive multiple comparisons correction; nonetheless, the results provide promising insight to the relationship between cortical thickness and navigation performance in healthy aging. Further cross-sectional and longitudinal investigations with a larger sample size are required to assess the impact of CRF and exercise on cortical thickness and navigation abilities in healthy aging. Understanding these relationships would contribute to the expansive body of literature that has linked CRF and exercise to neuroprotective mechanisms in the aging brain

Gray matter declines with age and hearing loss, but is partially maintained in tinnitus

The impact of age-related hearing loss extends beyond the auditory pathway and impacts brain areas related to cognitive impairment and even dementia. The presence of tinnitus, a sensation of sound that frequently co-occurs with hearing loss, is additionally linked to cognitive decline. Interestingly, structural neuroimaging studies have reported that hearing loss may precede or modulate the onset of cognitive impairment. In this study, we aimed to disentangle the effects of age, hearing loss, and tinnitus on gray matter structure. In total, 39 participants with hearing loss and tinnitus, 21 with hearing loss but without tinnitus, and 39 controls were included in this voxel- and surface-based morphometry MRI study. Whole brain volume and surface thickness measures were compared between the groups. Age-related gray matter volume decline was observed in all groups. Several brain areas showed smaller gray matter volume and cortical surface thickness in hearing loss without tinnitus, relative to controls. This reduction was observed both within and outside of the auditory pathway. Interestingly, these reductions were not observed in participants with tinnitus, who had similar hearing loss and were of similar age. Since we have tools to improve hearing loss, hearing screening may aid in the battle against cognitive decline