Brain Training and Meditation’s Effects on Memory in Subjects with Vascular Cognitive Impairment

Vascular Dementia (VaD) is an important public health concern, which causes significant morbidity and mortality amongst populations around the world. With the increases in average age of individuals and prevalence of cardiovascular risk factors, the incidence of vascular cognitive impairment (VCI) and VaD are on the rise. Most of this increase will come from cerebral small vessel disease (CSVD) as treatment for large vessel disease improves. Yet, very few interventions are recommended for CSVD beyond control of risk factors. In this thesis, we propose a non-pharmacological intervention, which we believe may address executive dysfunction in VCI due to CSVD. CSVD impairs functional frontal-subcortical connectivity and results in cognitive and functional impairments. Given the plasticity in these circuits, despite old age, cognitive training may be a good candidate for improving cognition in CSVD. However, previous studies have suffered from heterogeneity of pathologies in VCI by including both large and small vessel disease. Furthermore, they have often not considered the effects of anxiety and depression, which we aim to exclude from the study. Finally, these studies do not use validated composite scores as a primary endpoint and currently do not use any biomarkers to follow the progress of subjects. In this study, we aim to partially address these shortcomings and offer a more rigorous approach to cognitive training

Donepezil Impairs Memory in Healthy Older Subjects: Behavioural, EEG and Simultaneous EEG/fMRI Biomarkers

Rising life expectancies coupled with an increasing awareness of age-related cognitive decline have led to the unwarranted use of psychopharmaceuticals, including acetylcholinesterase inhibitors (AChEIs), by significant numbers of healthy older individuals. This trend has developed despite very limited data regarding the effectiveness of such drugs on non-clinical groups and recent work indicates that AChEIs can have negative cognitive effects in healthy populations. For the first time, we use a combination of EEG and simultaneous EEG/fMRI to examine the effects of a commonly prescribed AChEI (donepezil) on cognition in healthy older participants. The short- and long-term impact of donepezil was assessed using two double-blind, placebo-controlled trials. In both cases, we utilised cognitive (paired associates learning (CPAL)) and electrophysiological measures (resting EEG power) that have demonstrated high-sensitivity to age-related cognitive decline. Experiment 1 tested the effects of 5 mg/per day dosage on cognitive and EEG markers at 6-hour, 2-week and 4-week follow-ups. In experiment 2, the same markers were further scrutinised using simultaneous EEG/fMRI after a single 5 mg dose. Experiment 1 found significant negative effects of donepezil on CPAL and resting Alpha and Beta band power. Experiment 2 replicated these results and found additional drug-related increases in the Delta band. EEG/fMRI analyses revealed that these oscillatory differences were associated with activity differences in the left hippocampus (Delta), right frontal-parietal network (Alpha), and default-mode network (Beta). We demonstrate the utility of simple cognitive and EEG measures in evaluating drug responses after acute and chronic donepezil administration. The presentation of previously established markers of age-related cognitive decline indicates that AChEIs can impair cognitive function in healthy older individuals. To our knowledge this is the first study to identify the precise neuroanatomical origins of EEG drug markers using simultaneous EEG/fMRI. The results of this study may be useful for evaluating novel drugs for cognitive enhancement

Effet de la stimulation cholinergique sur la perception visuelle chez le rat et l'humain : études comportementales et électrophysiologiques

Le système cholinergique joue un rôle important dans de nombreuses fonctions cognitives telles que l'attention et l'apprentissage perceptuel. La stimulation pharmacologique du système cholinergique par le donépézil, un inhibiteur de l’acétylcholinestérase, est un moyen efficace pour améliorer les fonctions cognitives et le traitement cortical via les récepteurs muscariniques et nicotiniques. En effet, le donépézil permet l'accumulation d'acétylcholine dans la fente synaptique. Toutefois, l’effet de la stimulation pharmacologique du système cholinergique sur le traitement visuel complexe et l’apprentissage perceptuel n’est pas encore bien défini. L'objectif de cette thèse est d'étudier, d'une part, l'effet de la combinaison d’un entrainement visuel répétitif avec une stimulation cholinergique sur les capacités visuelles chez le rat et l’humain et, d'autre part, l’effet de la stimulation pharmacologique du système cholinergique sur la restauration des capacités visuelles dans un modèle de déficit visuel chez les rats. Nos résultats ont montré qu’un entrainement visuel/cholinergique entraînait : 1) une potentialisation à long terme de la réponse visuelle corticale chez le rat, 2) une récupération plus rapide des capacités visuelles chez la rat suite un écrasement du nerf optique 3) une amélioration de la performance dans une tâche perceptivo-cognitive de haut niveau plus rapide et conservée dans le temps chez les jeunes sujets sains. Le patron d’électroencéphalographie chez le sujet humain pratiquant une tâche d’attention visuelle n’est cependant pas modifié par l’administration d’une dose unique de donépézil. Ensembles, ces résultats soulignent le bénéfice considérable de la combinaison d’une stimulation du système cholinergique lors de l’entrainement visuel répétitif afin d'obtenir des améliorations de la perception visuelle. Cela présente une avenue très intéressante pour la réhabilitation chez les humains.The cholinergic system plays an important role in many cognitive functions such as attention and perceptual learning. Pharmacological stimulation of the cholinergic system via donepezil, an acetylcholinesterase inhibitor, is an efficient tool for enhancing cognitive functions and cortical processing via muscarinic and nicotinic receptors. In fact, donepezil allows the build-up of acetylcholine in the synaptic cleft. However, whether pharmacological manipulation of the cholinergic system has an effect on complex visual processing and perceptual learning remains unclear. The goal of this thesis is to investigate on the one hand the effect of combining repetitive visual training with cholinergic enhancement on visual capacities in rats and humans and on the other hand the effect of the pharmacological stimulation of the cholinergic system on visual restoration in a model of visual deficit in rats. Our results showed that cholinergic potentiation induces 1) a long-term potentiation of visual cortical response following repetitive visual stimulation, 2) a faster recovery of brightness discrimination in rats with an optic nerve crush, 3) a faster progression of and a sustained performance in a highly demanding perceptual-cognitive task for healthy young humans. However, the EEG pattern for subjects performing a visual attention task is not modified by a single administration of donepezil. Together these results underline the substantial benefice of combining cholinergic enhancement with visual training in order to obtain visual perception improvements, which presents an interesting avenue for visual rehabilitation paradigm in humans

Turning the spotlight to cholinergic pharmacotherapy of the human language system

Even though language is essential in human communication, research on pharmacological therapies for language deficits in highly prevalent neurodegenerative and vascular brain diseases has received little attention. Emerging scientific evidence suggests that disruption of the cholinergic system may play an essential role in language deficits associated with Alzheimer's disease and vascular cognitive impairment, including post-stroke aphasia. Therefore, current models of cognitive processing are beginning to appraise the implications of the brain modulator acetylcholine in human language functions. Future work should be directed further to analyze the interplay between the cholinergic system and language, focusing on identifying brain regions receiving cholinergic innervation susceptible to modulation with pharmacotherapy to improve affected language domains. The evaluation of language deficits in pharmacological cholinergic trials for Alzheimer's disease and vascular cognitive impairment has thus far been limited to coarse-grained methods. More precise, fine-grained language testing is needed to refine patient selection for pharmacotherapy to detect subtle deficits in the initial phases of cognitive decline. Additionally, noninvasive biomarkers can help identify cholinergic depletion. However, despite the investigation of cholinergic treatment for language deficits in Alzheimer's disease and vascular cognitive impairment, data on its effectiveness are insufficient and controversial. In the case of post-stroke aphasia, cholinergic agents are showing promise, particularly when combined with speech-language therapy to promote trained-dependent neural plasticity. Future research should explore the potential benefits of cholinergic pharmacotherapy in language deficits and investigate optimal strategies for combining these agents with other therapeutic approaches.Funding for open access publishing: Universidad Málaga/CBUA. Guadalupe Dávila was supported by the Junta de Andalucía, Spain (Grant: P20_00501). Marcelo L. Berthier has been supportedby the European Social Fund (FEDER: EQC2018-004803-P). María José Torres-Prioris was supported by a Margarita Salas postdoctoral fellowship by the University of Malaga, funded by the European Union, NextGenerationEU, and the Spanish Ministerio de Universidades. Diana López-Barroso was supported by the Ayuda RYC2020-029495-I Ramón y Cajal funded by the MCIN/AEI/10.13039/501100011033 and by El FSE invierte en tu futuro; and by the Grant PID2021-127617NAI00 Proyecto de Generación de Conocimiento 2021 funded by MCIN/AEI/10.13039/501100011033 and FEDER Una manera de hacerEuropa. Funding for the open access charge: Universidad de Málaga/CBU

Innovative cholinergic compounds for the treatment of cognitive dysfunction

The current symptomatic treatment for cognitive dysfunction due to dementia (eg Alzheimer's disease) is moderately effective and causes dose limiting side effects. This thesis describes the phase 1 development of new symptomatic treatments; Gln-1062 (pro-drug of galantamine) and HTL0009936 and HTL0018318 (both M1 muscarinic receptor partial agonists). Additionally, a new methodology was investigated, which can be applied when demonstrating pharmacological effects (biperiden challenge model), and a review of all biomarkers that were used to measure cholinergic effects is presented.LUMC / Geneeskund

Neurological and Mental Disorders

Mental disorders can result from disruption of neuronal circuitry, damage to the neuronal and non-neuronal cells, altered circuitry in the different regions of the brain and any changes in the permeability of the blood brain barrier. Early identification of these impairments through investigative means could help to improve the outcome for many brain and behaviour disease states.The chapters in this book describe how these abnormalities can lead to neurological and mental diseases such as ADHD (Attention Deficit Hyperactivity Disorder), anxiety disorders, Alzheimer’s disease and personality and eating disorders. Psycho-social traumas, especially during childhood, increase the incidence of amnesia and transient global amnesia, leading to the temporary inability to create new memories.Early detection of these disorders could benefit many complex diseases such as schizophrenia and depression

Cholinergic system in sequelae of traumatic brain injury

Background: Traumatic brain injury (TBI) is one of the most significant causes of disability and lowered capacity. TBI cause also a considerable financial burden since the majority of patients are young at the time of injury. Though much scientific work has been conducted, the pathophysiological mechanisms behind the sequelae of TBI are still largely unknown. However, there is evidence emerging from experimental and clinical studies that the cholinergic system seems to be at least partly involved in the cognitive impairment associated with TBI. In the TBI aftermath, patients commonly experience problems with attention, initiative and processing speed, i.e. functions which are mainly regulated by the cholinergic system. Additionally, in particular there are indications that the structures containing acetylcholinecontaining neurons are commonly injured in TBI. Furthermore, there is preliminary evidence that at least some TBI patients may benefit from cholinergic medication. Aims of the study: Our aim was to utilize positron emission tomography (PET) and magnetic resonance imaging (MRI) to evaluate possible alterations in the cholinergic system after TBI. An additional goal was to clarify the association of these structural or functional changes to the patient’s response to cholinergic medication. Patients with moderate-to-severe TBI were compared to healthy controls with PET using the [11C]MP4A tracer. MP4A targets acetylcholinesterase (AChE), which is the pre- and post-synaptic acetylcholine degrading enzyme. The TBI patient group was divided into two depending on their response to rivastigmine (inhibitor of AChE) treatment. These patient groups were imaged with MP4A-PET at baseline (without medication) and after 4 weeks of rivastigmine therapy to compare differences in AChE activity. Cholinergic structures were also investigated with atlas-based MRI morphometry. It was also examined whether the atrophy rates of frontal cholinergic structures were associated with neuropsychological tests results. The subjects filled in a questionnaire to determine whether their smoking histories had any connection to the outcome of TBI. Results: The AChE activity in TBI patients was clearly lowered in cortical regions when compared to controls. Most significantly, AChE activity was reduced in parieto- and occipital-cortices. A comparison of the two TBI patient groups in the primary time point scan showed evidence of lowered AChE activity in frontal cortical structures in rivastigmine responders. However, the inhibitory effect of rivastigmine on AChE activity was similar with patient groups when scanned during drug therapy and there was no longer any significant difference between groups in their AChE activities. MRI morphometry revealed that the higher the atrophy rate in frontal cortical structures, the poorer the performance in neuropsychological tests measuring attention. Smoking history was not associated with TBI outcome. Conclusions: According to the results of this study, it appears that the cholinergic system is altered chronically after TBI. It also seems that these structural alterations and the consequential functional changes in the cholinergic system are connected to the response to cholinergic medication. Additionally, the atrophy rate of frontal cortical structures, which are mainly innervated by cholinergic neurons, appears to have correlation to neuropsychological performance concerning attention. There did not seem to be any link between smoking and TBI outcome

L’effet d’une potentialisation cholinergique sur la régionalisation et la synchronisation corticale d’un conditionnement visuel

Cette thèse démontre qu’une potentialisation cholinergique durant un conditionnement visuel typique permet de raffiner la réponse et la connectivité des neurones des aires corticales visuelles ainsi que des aires associatives supérieures via un phénomène plastique. Afin de déterminer cet effet sur un conditionnement visuel monoculaire sur la réponse corticale, nous avons utilisé un système d’imagerie calcique à large champ sur des souris adultes exprimant le rapporteur calcique GCaMP6s. La potentialisation cholinergique était causée par l’administration de donepezil (DPZ), un inhibiteur de l’acétylcholinestérase qui dégrade l’acétylcholine. Cette technique, possédant de bonnes résolutions spatiale et temporelle, a permis l’observation de l’activité neuronale dans les couches supra granulaires du cortex visuel primaire (V1), des aires secondaires (A, AL, AM, LM, PM, RL) ainsi que dans le cortex retrosplénial (RSC). Il a été alors possible de mesurer les modifications d’activité neuronale de ces aires au repos et lors de la présentation de stimulations visuelles, composées de réseaux sinusoïdaux d’orientation et de contraste varié. La réponse corticale des animaux naïfs est similaire en matière d’amplitude et de sensibilité au contraste pour chacune des orientations de stimulations visuelles présentées. Le conditionnement visuel accompagné de l’administration de DPZ diminue significativement la réponse neuronale évoquée par le stimulus conditionné dans la majorité des aires observés alors qu’il ne modifie pas la réponse à la stimulation non conditionnée. Cet effet n’est pas présent sans potentialisation cholinergique. Il est intéressant de noter qu’un effet sur la corrélation d’activation est observé exclusivement dans les aires de la voie visuelle ventrale. Finalement, le conditionnement monoculaire diminue la corrélation au repos entre les aires visuelles monoculaire et binoculaire de chacun des hémisphères, un effet qui disparaît lors de l’administration du DPZ durant le conditionnement. En conclusion, nos résultats démontrent une diminution de l’amplitude et de l’étalement de la réponse corticale dans les couches supra-granulaires de PM et de V1 en réponse à notre traitement. Nous suggérons que ces résultats démontrent une diminution de la réponse excitatrice causée par l’augmentation de l’activité inhibitrice en réponse à la stimulation conditionnée.The cholinergic system of the basal forebrain modulates the visual cortex and enhances visual acuity and discrimination when activated during visual conditioning. As wide-field calcium imaging provides cortical maps with a fine regional and temporal resolution, we used this technique to determine the effects of the cholinergic potentiation of visual conditioning on cortical activity and connectivity in the visual cortex and higher associative areas. Mesoscopic calcium imaging was performed in head-fixed GCaMP6s adult mice during resting state or monocular presentation of conditioned (0.03 cpd, 30°, 100% contrast) or non-conditioned 1Hz-drifting gratings (30°, 50 and 75% contrast; 90°, 50, 75 and 100% contrast), before and after conditioning. The conditioned stimulus was presented 10 min daily for a week. Donepezil (DPZ, 0.3 mg/kg, s.c.), a cholinesterase inhibitor that potentiates cholinergic transmission, or saline were injected prior to each conditioning session and compared to a sham-conditioned group. Cortical maps were established, then amplitude, duration, and latency of the peak response, as well as size of activation were measured in the primary visual cortex (V1), secondary visual areas (AL, A, AM, PM, LM, RL), the retrosplenial cortex (RSC) , and higher cortical areas. Visual stimulation increased calcium signaling in all primary and secondary visual areas, but no other cortices (except RSC). The cortical responses were sensitive to contrast but not to grating orientation. There were no significant effects of sham-conditioning or conditioning alone, but DPZ treatment during conditioning significantly decreased the evoked neuronal activity response for the conditioned stimulus in V1, AL, PM, and LM. The size of activated area and signal-to-noise ratio were affected in some cortical areas. There was no effect for the non-conditioned stimuli. Interestingly, signal correlation appeared only between V1 and the ventral visual pathway and RSC and was decreased by DPZ administration. The resting state activity was slightly correlated and rarely affected by treatments, except between binocular and monocular V1 in both hemispheres. In conclusion, despite the previously observed enhancement of the cortical response of layer 4 after visual conditioning with cholinergic potentiation, mesoscale cortical calcium imaging showed that cholinergic potentiation diminished the cortical activation in layer 2/3 and sharpened the responses to the conditioned visual stimulus in V1 and PM, via a layer-dependent effect

Measures of Resting State EEG Rhythms for Clinical Trials in Alzheimer’s Disease:Recommendations of an Expert Panel

The Electrophysiology Professional Interest Area (EPIA) and Global Brain Consortium endorsed recommendations on candidate electroencephalography (EEG) measures for Alzheimer's disease (AD) clinical trials. The Panel reviewed the field literature. As most consistent findings, AD patients with mild cognitive impairment and dementia showed abnormalities in peak frequency, power, and "interrelatedness" at posterior alpha (8-12Hz) and widespread delta (<4Hz) and theta (4-8Hz) rhythms in relation to disease progression and interventions. The following consensus statements were subscribed: (1) Standardization of instructions to patients, resting state EEG (rsEEG) recording methods, and selection of artifact-free rsEEG periods are needed; (2) power density and "interrelatedness" rsEEG measures (e.g., directed transfer function, phase lag index, linear lagged connectivity, etc.) at delta, theta, and alpha frequency bands may be use for stratification of AD patients and monitoring of disease progression and intervention; and (3) international multisectoral initiatives are mandatory for regulatory purposes

Effects of cholinesterase inhibition on brain function

Pharmacological-functional imaging provides a non-invasive method by which the actions of neurotropic drugs on the human brain can be explored. Simply put, it assesses how neural activity patterns associated with cognitive functions of interest are modified by a drug challenge. Since one of the most widely-used cognitive-enhancing drugs in clinical practice are cholinesterase inhibitors, this thesis applies pharmacological functional imaging to the question of understanding how such drugs work - both in healthy people and dementia. The experiments in this thesis describe how brain activations – as revealed by functional magnetic resonance imaging (fMRI) – are modulated by the cholinesterase inhibitor physostigmine, during tasks designed to isolate sensory, attentional, and memory processes. While non-human and human psychophysical studies suggest that all three of these cognitive functions are under the control of the endogenous cortical cholinergic system, understanding how neurobiological models of cholinergic function translate into human brain activation modulations is unclear. One main question that is particularly relevant in this regard, that recurs through all the experiments, is how physostigmine-induced neuromodulations differ between sensory-driven ‘bottom-up’, and task-driven ‘top-down’, brain activations. The results are discussed with reference both to non-human physiological data and to existing human cholinergic-functional imaging studies (fifty studies published to date), which are themselves reviewed at the outset. Furthermore, assumptions based upon the physical and physiological principles of pharmacological functional imaging, being critical to interpretation, are discussed in detail within a general methods section