Brain oscillations and novelty processing in human spatial memory

Hippocampal activity in rodent model systems is commonly associated with movement and exploratory behaviour, while human hippocampal research has traditionally focused on mnemonic function. I attempted to bridge this gap with a set of experiments where human participants performed an interactive virtual navigation paradigm that resembled rodent spatial exploration tasks, in conjunction with neuroimaging techniques such as functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG). I then used this interactive paradigm to examine the oscillatory correlates of memory, novelty and the behavioural relevance of the default mode network. The first experiment used MEG and fMRI to examine whether the movement-related theta rhythm (4-8 Hz) recorded from the rodent hippocampus has a measurable human analog. I found that the human hippocampal theta rhythm supports memory, and may coordinate exploratory movements in the service of self-directed learning. In further analyses in Experiment 2, during cued spatial memory retrieval, I observed that medial prefrontal cortex theta phase couples with ongoing theta oscillations in the right anterior medial temporal lobe and with neocortical gamma (65-85 Hz) amplitude. In Experiment 3, with fMRI I investigated the effect of environmental novelty versus object novelty during the navigation task and found that hippocampal activity is modulated only by environmental novelty, while the fusiform gyrus/posterior parahippocampal cortex responded to object novelty. Finally, in Experiment 4 using 3T and high-field 7T fMRI, I investigated endogenous (task-free) periods that flanked different stages of a spatial navigation paradigm to determine how endogenous slow oscillations in the default mode network correlate with subsequent spatial memory performance and found mixed evidence that default mode network activity predicts individual performance. Finally, I discuss my results in the context of recent findings in spatial memory and novelty processing, and consider the relationship between the human hippocampus and rodent model systems

Amygdala and fusiform gyrus temporal dynamics: Responses to negative facial expressions

<p>Abstract</p> <p>Background</p> <p>The amygdala habituates in response to repeated human facial expressions; however, it is unclear whether this brain region habituates to schematic faces (i.e., simple line drawings or caricatures of faces). Using an fMRI block design, 16 healthy participants passively viewed repeated presentations of schematic and human neutral and negative facial expressions. Percent signal changes within anatomic regions-of-interest (amygdala and fusiform gyrus) were calculated to examine the temporal dynamics of neural response and any response differences based on face type.</p> <p>Results</p> <p>The amygdala and fusiform gyrus had a within-run "U" response pattern of activity to facial expression blocks. The initial block within each run elicited the greatest activation (relative to baseline) and the final block elicited greater activation than the preceding block. No significant differences between schematic and human faces were detected in the amygdala or fusiform gyrus.</p> <p>Conclusion</p> <p>The "U" pattern of response in the amygdala and fusiform gyrus to facial expressions suggests an initial orienting, habituation, and activation recovery in these regions. Furthermore, this study is the first to directly compare brain responses to schematic and human facial expressions, and the similarity in brain responses suggest that schematic faces may be useful in studying amygdala activation.</p

Dopaminergic and Non-Dopaminergic Value Systems in Conditioning and Outcome-Specific Revaluation

Animals are motivated to choose environmental options that can best satisfy current needs. To explain such choices, this paper introduces the MOTIVATOR (Matching Objects To Internal Values Triggers Option Revaluations) neural model. MOTIVATOR describes cognitiveemotional interactions between higher-order sensory cortices and an evaluative neuraxis composed of the hypothalamus, amygdala, and orbitofrontal cortex. Given a conditioned stimulus (CS), the model amygdala and lateral hypothalamus interact to calculate the expected current value of the subjective outcome that the CS predicts, constrained by the current state of deprivation or satiation. The amygdala relays the expected value information to orbitofrontal cells that receive inputs from anterior inferotemporal cells, and medial orbitofrontal cells that receive inputs from rhinal cortex. The activations of these orbitofrontal cells code the subjective values of objects. These values guide behavioral choices. The model basal ganglia detect errors in CS-specific predictions of the value and timing of rewards. Excitatory inputs from the pedunculopontine nucleus interact with timed inhibitory inputs from model striosomes in the ventral striatum to regulate dopamine burst and dip responses from cells in the substantia nigra pars compacta and ventral tegmental area. Learning in cortical and striatal regions is strongly modulated by dopamine. The model is used to address tasks that examine food-specific satiety, Pavlovian conditioning, reinforcer devaluation, and simultaneous visual discrimination. Model simulations successfully reproduce discharge dynamics of known cell types, including signals that predict saccadic reaction times and CS-dependent changes in systolic blood pressure.Defense Advanced Research Projects Agency and the Office of Naval Research (N00014-95-1-0409); National Institutes of Health (R29-DC02952, R01-DC007683); National Science Foundation (IIS-97-20333, SBE-0354378); Office of Naval Research (N00014-01-1-0624

Novelty Enhances Visual Perception

The effects of novelty on low-level visual perception were investigated in two experiments using a two-alternative forced-choice tilt detection task. A target, consisting of a Gabor patch, was preceded by a cue that was either a novel or a familiar fractal image. Participants had to indicate whether the Gabor stimulus was vertically oriented or slightly tilted. In the first experiment tilt angle was manipulated; in the second contrast of the Gabor patch was varied. In the first, we found that sensitivity was enhanced after a novel compared to a familiar cue, and in the second we found sensitivity to be enhanced for novel cues in later experimental blocks when participants became more and more familiarized with the familiar cue. These effects were not caused by a shift in the response criterion. This shows for the first time that novel stimuli affect low-level characteristics of perception. We suggest that novelty can elicit a transient attentional response, thereby enhancing perception

The neuroscience of fear and anxiety: a primer for clinicians

Over the last few decades, research in affective neuroscience has led to considerable insights into the biology of fear and anxiety. For those in the practice of psychotherapy, these advances hold the potential for explaining the evolutionary utility of these emotions and targeting psychotherapeutic interventions to neurobiological correlates when these emotions go awry. The conversation of neuroscience, however, has yet to find a comfortable place in the therapy room. Translational and conceptual disparities owing to the historical split between psychology and neuroscience, continue to present challenges to their integration. The present study seeks to reframe clinicians’ understanding of the biological underpinnings of fear and anxiety from a static model governed by genetic predisposition and chemical imbalances, to a dynamic process that focuses on the environment’s impact on biology. The following topics will be addressed: What are the neurobiological processes of fear and anxiety? Why did they evolve to serve adaptive purposes? What are the conditions in which disorders of anxiety and fear emerge? To answer these questions, this review of the literature discusses how fear and anxiety centers in the mammalian brain were shaped through phylogenetic development to respond to physical and interpersonal threat, and how fear and anxiety continue to benefit in learning and defensive action. An updated view of the neuroscience of fear and anxiety is also reviewed detailing the functions of known structures and involved pathways. Risk factors for panic and anxiety disorders, the neurological impacts of failure of coping with fear and anxiety are explored, and the application of psychotherapy are discussed. These findings will be applied towards a concise handbook on the neuroscience of fear and anxiety to provide a narrative of an adaptive model for use in the therapy room

The Distribution of Toxoplasma gondii Cysts in the Brain of a Mouse with Latent Toxoplasmosis: Implications for the Behavioral Manipulation Hypothesis

reportedly manipulates rodent behavior to enhance the likelihood of transmission to its definitive cat host. The proximate mechanisms underlying this adaptive manipulation remain largely unclear, though a growing body of evidence suggests that the parasite-entrained dysregulation of dopamine metabolism plays a central role. Paradoxically, the distribution of the parasite in the brain has received only scant attention. at six months of age and examined 18 weeks later. The cysts were distributed throughout the brain and selective tropism of the parasite toward a particular functional system was not observed. Importantly, the cysts were not preferentially associated with the dopaminergic system and absent from the hypothalamic defensive system. The striking interindividual differences in the total parasite load and cyst distribution indicate a probabilistic nature of brain infestation. Still, some brain regions were consistently more infected than others. These included the olfactory bulb, the entorhinal, somatosensory, motor and orbital, frontal association and visual cortices, and, importantly, the hippocampus and the amygdala. By contrast, a consistently low incidence of tissue cysts was recorded in the cerebellum, the pontine nuclei, the caudate putamen and virtually all compact masses of myelinated axons. Numerous perivascular and leptomeningeal infiltrations of inflammatory cells were observed, but they were not associated with intracellular cysts. distribution stems from uneven brain colonization during acute infection and explains numerous behavioral abnormalities observed in the chronically infected rodents. Thus, the parasite can effectively change behavioral phenotype of infected hosts despite the absence of well targeted tropism

Nucleus Basalis of Meynert Stimulation for Dementia: Theoretical and Technical Considerations

Deep brain stimulation (DBS) of nucleus basalis of Meynert (NBM) is currently being evaluated as a potential therapy to improve memory and overall cognitive function in dementia. Although, the animal literature has demonstrated robust improvement in cognitive functions, phase 1 trial results in humans have not been as clear-cut. We hypothesize that this may reflect differences in electrode location within the NBM, type and timing of stimulation, and the lack of a biomarker for determining the stimulation’s effectiveness in real time. In this article, we propose a methodology to address these issues in an effort to effectively interface with this powerful cognitive nucleus for the treatment of dementia. Specifically, we propose the use of diffusion tensor imaging to identify the nucleus and its tracts, quantitative electroencephalography (QEEG) to identify the physiologic response to stimulation during programming, and investigation of stimulation parameters that incorporate the phase locking and cross frequency coupling of gamma and slower oscillations characteristic of the NBM’s innate physiology. We propose that modulating the baseline gamma burst stimulation frequency, specifically with a slower rhythm such as theta or delta will pose more effective coupling between NBM and different cortical regions involved in many learning processes

Indiviididevahelised erinevused depressioonisoodumuses: aju regionaalne energiametabolism, serotoniinisüsteemi talitlus ja käitumine loomkatsemudelites

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Käesolev doktoriväitekiri keskendub depressiooni funktsionaalse neuroanatoomia ja depressiivse käitumise uurimisele, kasutades meeleoluhäirete loomkatsemudeleid. Depressiooni põhjustavad nii korduvad stressirikkad elusündmused kui ka individuaalne soodumus ja eelkõige nende kahe teguri koosmõju. Depressioonisoodumust saab mudeldada selekteerides rotte afektiivse käitumise testide alusel või mõjustades pikaajaliselt nende ajus depressiooni tõenäolisi neuraalseid alusmehhanisme. Käesolevas väitekirjas käsitletakse nelja depressioonisoodumuse mudelit - osaline serotonergiline närvikahjustus, puudulik emahool vastsündinueas, vähene püsi-sotsiaalsus ja püsiv magusaeelistus. Keskkonnast tuleneva stressi mudeldamiseks kasutati kroonilist muutlikku stressi, mille depressiooni-põhjustav mõju rajaneb mitmete mõõdukalt ebameeldivate stiimulite korduval esitamisel, ja kroonilist sotsiaalset stressi, mis rajaneb looma korduval alistamisel agressiivse liigikaaslase poolt. Ajupiirkondade pikaajalise närviaktiivsuse määramiseks hinnati mitokondriaalse elektronide transpordi-ahela talitlust tsütokroom c oksüdaasi aktiivsuse histokeemilise mõõtmise kaudu. Kõik depressioonisoodumuse ja kroonilise stressi mudelid eraldiseisvaina põhjustasid mõnedes ajupiirkondades muutuse närviaktiivsuses, kuid eri mudelite piirkondlikud aktivatsioonimustrid ei kattunud. Kui kroonilist stressi rakendati depressioonisoodumusega loomadele, ilmnesid mudelitevahelised kokkulangevused närviaktiivsuses eesmises taalamuses, hippokampuse CA3 alas ja mediaalses mandelkehas, s.o. piirkondades, mis on kesksel kohal organismi stressivastuse, õppimise ja hirmuga seotud käitumiste kontrollis. Kui tsütokroom c oksüdaasi aktiivsuse andmeid erinevatest katsetest koos analüüsiti, ilmnes, et depresioonisoodumusega rottidel oli närvitegevus aktiivsem retro-spleniaalses ajukoores ja retikulaarses taalamuses, krooniline stress aga taandas selle aktiivsuse kontroll-loomadega samale tasemele. Funktsionaalse ühenduvuse analüüs näitas, et depressioonisoodumus ja krooniline stress nõrgendasid ajupiirkondadevahelist seotust haistesibulate, tsentraalse mandelkeha, terminaaljuti sängituumade, prefrontaalkoore ja vöökääruga seotud ajuringetes. Käesolev töö tõi välja mitmeid ajupiirkondi, mida tasuks üksikasjalikumalt edasi uurida, nagu näiteks võrgustik, mis hõlmab eesmist taalamust, retrospleniaalset ajukoort, eesmist vöökääru, hippokampust ja retikulaarset taalamust.This doctoral dissertation focuses on the functional neuroanatomy and behaviour in animal models of affective disorders. Depression is caused by stressful life events, by inherent individual vulnerability, and most potently by a combination of these two factors. Vulnerability to depression can be modelled in rats by selection in behavioural tests for a trait related to low affect or by experimentally producing a neurobiological state that possibly serves as the substrate of depression. In this dissertation four vulnerability phenotypes were studied - partial serotonergic denervation, neonatal maternal separation, low expression of the sociability trait and sucrose preference trait. Environmental stress was induced by chronic variable stress that led to a depressive state by repeated administration of several mildly noxious stimuli to the animal, and chronic social stress, that is based on the repeated social defeat of the target animal by an aggressive congener. To detect cerebral regional long-term neural activation the function of mitochondrial electron transport chain was assessed via cytochrome c oxidase histochemistry. All the vulnerability phenotypes and chronic stress regimens caused a change in long-term neuronal activity on their own in specific brain regions, but there was no overlap between the regional activity patterns in different models. When chronic stressors were applied in combination with vulnerability factors, communalities between different models in energy metabolism were detected in anterior thalamus, hippocampal CA3 area and medial amygdala, areas crucially involved in stress response, fear and learning. When cytochrome oxidase activity data from all models were collapsed and analysed jointly, it was revealed that rats with the vulnerable phenotype had more active energy metabolism in retrosplenial cortex and reticular thalamus, and stress reversed this activation to control-like levels. Functional connectivity analysis revealed that vulnerability phenotypes and chronic stress decreased inter-regional connectivity in the brain circuits including olfactory bulbi, central amygdala, bed nucleus of stria terminalis, prefrontal and cingulate cortices. Thus this work has indicated several new anatomical targets for more detailed study, for example the highly interconnected nuclei of anterior thalamus, retrosplenial cortex, anterior cingulate, hippocampus and reticular thalamus

The Effect of Selective Cholinergic Lesion of Medial Septum on Recognition Memory

The objective of this study was to clarify the role of septal-hippocampal cholinergic neurons in object and spatial recognition memory. Stereotaxic-surgical infusion of the selective cholinergic neurotoxin, 192IgG-saporin (SAP), into the medial septum (MS) of Sprague-Dawley rats was utilized to establish an animal model of cholinergic deficit of the septal-hippocampal tract, which had been expected as a pathologic model of memory impairment for Alzheimer\u27s disease (AD). Three types of recognition memory were examined: retrograde object recognition, anterograde object recognition, and anterograde spatial recognition. These were examined with a modified version of a standard object recognition paradigm. For retrograde memory retention testing, rats received SAP after training; in contrast, for anterograde retention testing, rats received SAP before training. The time that the rats spent exploring familiar and novel objects or familiar objects in a novel location was measured. The effects of SAP on the three types of recognition memory were tested and compared to control animals. There was no significant difference in the mean exploration ratios (MERs) between control rats infused with artificial cerebrospinal fluid (aCSF) and control rats that did not receive surgery (NOR). The MERs for both control groups were in the range between 0.6-0.7, consistent with the object recognition testing literature. These results indicate that the infusion surgery itself had no effect on object or spatial recognition memory and that the methodology for object and spatial recognition developed for this study worked well. SAP lesioned rats did not demonstrate impairment of retrograde object recognition memory (0.68±0.04 vs 0.67±0.03, p = 0.888) and also displayed normal anterograde object recognition memory (0.67±0.04 vs 0.66±0.02, p = 0.866) compared to control rats. However, compared to controls, SAP rats were significantly impaired in anterograde spatial recognition memory as reflected in the fall of the MER for the SAP group to chance levels (0.51±0.04 vs 0.62±0.02. p = 0.0081). These findings suggest that the septal-hippocampal cholinergic neurons play an important role for spatial recognition memory, but not for object recognition memory and indicate that the septal-hippocampal cholinergic deficit may be responsible for the mild memory impairments shown in the early phase of AD