Orienting behaviours and attentional processes in the mouse and macaque : neuroanatomy, electrophysiology and optogenetics

PhD ThesisThe neuronal basis of orienting and attentional behaviours has been widely researched in higher animals such as non-human primates (NHPs). However the organisation of these behaviours and processes in rodent models has been less well characterised. This thesis is motivated to delineate the key neuroanatomical pathways and neuronal mechanisms that account for orienting behaviours in the mouse model and compare them, in part, to those seen in the macaque. A better understanding of the processes and networks involved with attention and orienting is necessary in order to relate findings in the mouse model to those seen in humans and NHPs. Further to this, the availability of highly targeted manipulations in the mouse, such as optogenetics, requires a more detailed picture of the neurophysiology underpinning those behaviours to effectively interpret findings and design experiments to exploit these techniques and animal models for maximum benefit. In this thesis, study one focuses on the neuroanatomical pathways that terminate in subregions of the midbrain superior colliculus (SC) in the mouse (mus musculus) using iontophoretic injection of the retrograde tracer fluorogold. This region has been implicated in various forms of orienting behaviours in both macaques and mice (Albano et al., 1982, Dean et al., 1988b, Felsen and Mainen, 2008). Furthermore study one examines the prefrontal connectivity that links to the SC subsections and which may govern approach and avoidance behaviours (motor cortex area 2 (M2) and cingulate area (Cg)) in the mouse via pressure injection of the anterograde tracer biotinylated dextran amine into these regions. It was found that the medial and lateral SC receive differential prefrontal input from the Cg and M2 respectively. And that these areas project to brain networks related to avoidance or approach. This section furthers our understanding of the partially segregated networks which exist in the prefrontal cortex and midbrain of the mouse, which are important in mediation of different orienting behaviours Study two focuses on the effects of one type of orienting, namely bottom-up attention (BU) in visual areas. This exogenous (automatic) form of visual attention has been studied extensively in human psychophysics (Posner, 1980, Nakayama and Mackeben, 1989) and the areas involved in the human brain have been delineated using brain imaging (Corbetta and Shulman, 2002, Liu et al., 2005). To understand the neurophysiology involved, some electrophysiological invasive studies have been performed in the macaque monkeys, II ( Luck et al., 1997, Buschman and Miller, 2007), but our understanding of the mechanisms involved is relatively sparse when compared to top-down (endogenous) attentional processing. To understand the similarities in this mechanism between macaques and mice it is therefore important to study both model systems using similar approaches. The research of this chapter aims to make direct comparisons between these two model species via electrophysiological recordings in a bottom-up attentional paradigm. It was found that in the macaque BU cues increased responses to visual stimuli in both V1 and V4, but no obvious pattern was seen in the mouse V1 and SC. This study goes some way in describing the similarities and differences in neural responses in visual areas of different species which are utilised for attention based paradigms Finally study three focuses on linking the previous two studies. In study two we investigated bottom-up attentional processes, which are thought to involve early, fast visuomotor pathways. Whereas in study one we found that SC and V1, areas known for their involvement in and ability to coordinate rapid visuomotor responses, respectively, also receive clear and structured input from higher-level prefrontal areas. Therefore we hypothesized that stimulating these prefrontal areas could modulate bottom-up attention. This is achieved by using optogenetic stimulation of prefrontal control regions, such as Cg, identified in this research whilst preforming electrophysiological recordings in a bottom-up attentional paradigm. In V1 is was found that optogenetic stimulation had no effect on neuronal activation. However in SC optogenetic activation increased the sustained stimulus response, regardless of cuing condition. Taken together, this research further investigates some brain regions involved in orienting and attention in both mice and macaques and partially bridges the gap in understanding between these two animal models

Functional MRI investigations of human temporoparietal junction: attention, response inhibition, theory of mind, and long-term meditation effects

The human cortical temporoparietal junction (TPJ) has been implicated in cognitive processes including attentional reorienting, social cognition, and behavioral inhibition. Functional organization of TPJ remains unclear due to individual differences in anatomy. This dissertation describes functional magnetic resonance imaging (fMRI) experiments examining TPJ at the level of individuals. A method to localize TPJ using fMRI in individual subjects was developed and tested. TPJ subregions for social cognition, behavioral inhibition, and attention reorienting were parcellated. Finally, differences in attention networks between practitioners of focused attention meditation and matched control participants were investigated. Fifty individuals (ages 20-58; 21 women) participated. Experiment 1 (n=10) developed and tested a novel fMRI paradigm ('CueBall') that combined two forms of attentional reorienting; participants directed and shifted attention in a spatial cueing task and were distracted by the infrequent and unexpected presentation of task-irrelevant images ('oddballs'). The contrast of 'oddball distractor' to 'non-oddball' trials robustly identified TPJ in individual brains. Bilateral subdivisions of TPJ were identified in the fundus of the superior temporal sulcus (STS) and in ventral supramarginal gyrus (SMG). Experiment 2 (n=10, including one individual from Experiment 1) employed the CueBall task along with a Stop Signal task and a Theory of Mind task to determine whether these disparate tasks recruit common or distinct cortical areas. The data demonstrated functional overlap in anterior TPJ between the attention and behavioral inhibition tasks and in posterior TPJ for attention and Theory of Mind. Experiment 3 (n=30) investigated neural correlates of focused attention meditation training in the dorsal attention network (DAN), the default mode network (DMN), and ventral attention network (VAN). Meditators demonstrated an increased magnitude of differential activation in DAN vs. DMN in a sustained attention task, relative to matched controls. In contrast, attentional reorienting did not reveal attention network differences between meditators and controls. Taken together, this work validates an attentional fMRI tool, helps disambiguate functional organization of the TPJ, and demonstrates neural correlates of improved attention in humans with meditation experience.2020-03-31T00:00:00

Modulation of behavior and brain activity by probabilistic inference

Expectancies and beliefs about upcoming sensory events encoded by the brain play a crucial role in shaping our perception. Therefore, stimulus detection and processing can be facilitated by prior beliefs about the stimulus’ location or its features. These beliefs are rapidly generated by former observations/experience of the individual. Bayesian principles can evidently be used to describe this probabilistic inference. The present thesis aimed to characterize the mechanisms underlying probabilistic inference in the healthy and the lesioned human brain. In healthy participants, probabilistic inference in the context of attentional deployment has already been described with the help of computational models, and the underlying neural mechanisms have been explored with functional neuroimaging (Dombert, Kuhns, et al., 2016; Kuhns et al., 2017; Vossel et al., 2015). However, it is not known how the resting-state network architecture of the brain relates to this process and how the lesioned brain performs probabilistic inference. To investigate these questions, two experiments have been conducted using modified versions of a Posner-cueing paradigm. In this context, probabilistic inference describes the ability to infer changing probabilities about the validity of a cue and the updating process of the belief about them. By manipulating the percentage of cue validity (%CV) (i.e., the proportion of valid and invalid trials) over the time course of an experiment, the participants had to infer the actual cue validity level (i.e., the probability that the cue will be valid in a given trial), so that probabilistic inference could be assessed. In Experiment 1, a modified location-cueing paradigm with block-wise changes of the %CV and true and false prior information about the %CV before each block was employed in healthy young participants. A Rescorla-Wagner model was used to characterize probabilistic inference. Moreover, resting-state fMRI was recorded before and after the task and a seedbased correlation analysis was used to define the resting-state functional connectivity (rsFC) of the right temporo-parietal junction (rTPJ). Correlations of each behavioral parameter with the rsFC before the task, as well as with changes in rsFC after the task, were assessed in a ROI-based approach. It was observed that higher intrahemispheric rsFC between rTPJ and IPS before the task was associated with slower probabilistic inference after false priors. Furthermore, increased interhemispheric rsFC between rTPJ and lTPJ after the task was related to relatively faster probabilistic inference in false blocks. Both findings support previous research and highlight that not only resting-state connectivity per se is relevant for cognitive functions but also that cognitive processing during a task can change connectivity patterns afterwards in a performance-dependent manner. In Experiment 2, probabilistic inference in stroke patients was investigated to assess a hypothesized relationship with the spatial neglect syndrome (Experiment 2a) as well as commonalities and distinctions between probabilistic inference in different cognitive subsystems (Experiment 2b). Three modified versions of the Posner-cueing task with different cue types were used to investigate spatial attention (location cues), feature-based attention (color cues) and motor-intention (motor-response cues). In contrast to Experiment 1, no prior information about the %CV was provided and probabilistic inference was operationalized by assessing the impact of the %CV manipulation on RTs by means of regression analyses as well as by asking participants to explicitly estimate the %CV. Furthermore, patients were screened for the neglect syndrome using a diverse neuropsychological test battery. Lesion-symptom mapping (VLSM) as well as lesion-network mapping was performed on the relevant behavioral parameters. The results indicated that patients’ probabilistic inference abilities across domains were not per se impaired. However, by trend it was found that some right hemisphere damaged patients exhibited difficulties using their knowledge to adapt their behavior in contralesional space as indicated by a reduced modulation of RTs by %CV in invalid contralesional trials in the spatial attention domain. However, there was no strong evidence for impairments of probabilistic inference being related to the neglect syndrome. Moreover, the correlation of the two probabilistic inference parameters (invalid contralesional %CV regression weight & averaged explicit %CV estimate) within domains revealed no significant relationship between the both, stating them as independent components of probabilistic inference, which was further supported by the VLSM results. However, the correlations across domains revealed some commonalities, which were also in line with the VLSM results. Thus, our data suggests that the neural implementations for probabilistic inference seem to be dedicated to domain-specific subsystems, which share some common nodes. Consequently, the present thesis provides novel insights into the computational mechanisms of probabilistic inference in the healthy and lesioned brain. The work thereby enables future studies to transfer the gained knowledge from basic research of healthy participants and patients to clinical applications

Neural correlates of fear: insights from neuroimaging

Fear anticipates a challenge to one's well-being and is a reaction to the risk of harm. The expression of fear in the individual is a constellation of physiological, behavioral, cognitive, and experiential responses. Fear indicates risk and will guide adaptive behavior, yet fear is also fundamental to the symptomatology of most psychiatric disorders. Neuroimaging studies of normal and abnormal fear in humans extend knowledge gained from animal experiments. Neuroimaging permits the empirical evaluation of theory (emotions as response tendencies, mental states, and valence and arousal dimensions), and improves our understanding of the mechanisms of how fear is controlled by both cognitive processes and bodily states. Within the human brain, fear engages a set of regions that include insula and anterior cingulate cortices, the amygdala, and dorsal brain-stem centers, such as periaqueductal gray matter. This same fear matrix is also implicated in attentional orienting, mental planning, interoceptive mapping, bodily feelings, novelty and motivational learning, behavioral prioritization, and the control of autonomic arousal. The stereotyped expression of fear can thus be viewed as a special construction from combinations of these processes. An important motivator for understanding neural fear mechanisms is the debilitating clinical expression of anxiety. Neuroimaging studies of anxiety patients highlight the role of learning and memory in pathological fear. Posttraumatic stress disorder is further distinguished by impairment in cognitive control and contextual memory. These processes ultimately need to be targeted for symptomatic recovery. Neuroscientific knowledge of fear has broader relevance to understanding human and societal behavior. As yet, only some of the insights into fear, anxiety, and avoidance at the individual level extrapolate to groups and populations and can be meaningfully applied to economics, prejudice, and politics. Fear is ultimately a contagious social emotion

Naturalistic driving measures of route selection associate with resting state networks in older adults

Our objective was to identify functional brain changes that associate with driving behaviors in older adults. Within a cohort of 64 cognitively normal adults (age 60+), we compared naturalistic driving behavior with resting state functional connectivity using machine learning. Functional networks associated with the ability to interpret and respond to external sensory stimuli and the ability to multi-task were associated with measures of route selection. Maintenance of these networks may be important for continued preservation of driving abilities

Neural correlates of egocentric and allocentric frames of reference combined with metric and non-metric spatial relations

Spatial relations (SRs: coordinate/metric vs categorical/non metric) and frames of reference (FoRs: egocentric/body vs allocentric/external element) represent the building blocks underlying any spatial representation. In the present 7-T fMRI study we have identified for the first time the neural correlates of the spatial representations emerging from the combination of the two dimensions. The direct comparison between the different spatial representations revealed a bilateral fronto-parietal network, mainly right sided, that was more involved in the egocentric categorical representations. A right fronto-parietal circuitry was specialized for egocentric coordinate representations. A bilateral occipital network was more involved in the allocentric categorical representations. Finally, a smaller part of this bilateral network (i.e. Calcarine Sulcus and Lingual Gyrus), along with the right Supramarginal and Inferior Frontal gyri, supported the allocentric coordinate representations. The fact that some areas were more involved in a spatial representation than in others reveals how our brain builds adaptive spatial representations in order to effectively react to specific environmental needs and task demands

Increased brain white matter axial diffusivity associated with fatigue, pain and hyperalgesia in Gulf War illness

Background Gulf War exposures in 1990 and 1991 have caused 25% to 30% of deployed personnel to develop a syndrome of chronic fatigue, pain, hyperalgesia, cognitive and affective dysfunction. Methods Gulf War veterans (n = 31) and sedentary veteran and civilian controls (n = 20) completed fMRI scans for diffusion tensor imaging. A combination of dolorimetry, subjective reports of pain and fatigue were correlated to white matter diffusivity properties to identify tracts associated with symptom constructs. Results Gulf War Illness subjects had significantly correlated fatigue, pain, hyperalgesia, and increased axial diffusivity in the right inferior fronto-occipital fasciculus. ROC generated thresholds and subsequent binary regression analysis predicted CMI classification based upon axial diffusivity in the right inferior fronto-occipital fasciculus. These correlates were absent for controls in dichotomous regression analysis. Conclusion The right inferior fronto-occipital fasciculus may be a potential biomarker for Gulf War Illness. This tract links cortical regions involved in fatigue, pain, emotional and reward processing, and the right ventral attention network in cognition. The axonal neuropathological mechanism(s) explaining increased axial diffusivity may account for the most prominent symptoms of Gulf War Illness

The Impact of Motivation on Object-Based Visual Attention Indexed by Continuous Flash Suppression.

Motivationally-relevant stimuli summon our attention and benefit from enhanced processing, but the neural mechanisms underlying this prioritization are not well understood. Using an interocular suppression technique and functional neuroimaging, this work has the ultimate aim of understanding how motivation impacts visual perception. In Chapter 2a, we demonstrate that novel objects with a more rich reward history are prioritized in awareness more quickly than objects with a lean reward history. In Chapter 2b, we show that faces are prioritized in awareness following social rejection, and that the amount faces are prioritized correlates with individual differences in social motivation. Chapters 3 & 4 use a combination of functional neuroimaging and flash suppression to suppress fearful faces and houses from awareness. Using binocular rivalry and motion flash suppression in Chapter 3, we find that suppressed fearful faces activate the amygdala relative to suppressed houses, and the amygdala increases coherence with a network of regions involved in attention, including bilateral pulvinar, bilateral insula, left frontal eye fields, left inferior parietal cortex, and early visual cortex. Using the more robust technique, continuous flash suppression, in Chapter 4, we find no differentiation between stimuli based on mean amygdala responses. However, we show increased connectivity between the amygdala, the pulvinar, and inferior parietal cortex specific to fearful faces. Overall, these results indicate that motivationally-relevant stimuli activate the amygdala prior to awareness. Enhanced connectivity between the amygdala and regions involved in attention may underlie the enhanced processing seen for salient stimuli

Neural correlates of visual awareness

openL'elaborato si propone di esporre le attuali evidenze riguardanti il modo in cui i contenuti soggettivi di consapevolezza visiva sono codificati a livello neurale. Sebbene i meccanismi neurali della percezione visiva siano ampiamente conosciuti, rimane ancora da chiarire come l'informazione visiva entri a far parte dei contenuti della coscienza. Per identificare i correlati neurali della coscienza (CNC), che rappresentano la minima attività neurale per una specifica esperienza conscia, vengono messe in relazione misure comportamentali di consapevolezza, limitatamente a stimoli presentati in un contesto sperimentale, con i sottostanti meccanismi neurali. Attraverso paradigmi sperimentali come la rivalità binoculare e tecniche di mascheramento visivo è possibile provare ad identificare i CNC contenuto-specifici utilizzando misure neurofisiologiche e tecniche di neuroimaging. Tali tecniche forniscono infatti utili informazioni circa le basi neuroanatomiche e funzionali dell'esperienza sotto esame. Sebbene i meccanismi che sottendono l’attenzione siano spesso associati all'esperienza cosciente, evidenze sperimentali suggeriscono una separazione tra i due processi. Le ricerche sui correlati neurali della consapevolezza visiva indicano come l’attività di una singola area cerebrale non possa essere necessaria e sufficiente a spiegare le qualità dei contenuti coscienti. Sembrerebbe invece essere necessaria una rappresentazione della scena visiva distribuita nella corteccia visiva primaria (V1) e nelle aree visive ventrali con attivazione di regioni temporo-parietali. Misure elettrofisiologiche come la visual awareness negativity (VAN) sono state correlate alla consapevolezza visiva mentre altri indicatori sembrerebbero essere maggiormente legati a processi attentivi. Diversi modelli teorici offrono spiegazioni empiriche sull’emergenza della coscienza dall’attività cerebrale. Nel caso della consapevolezza visiva, alcuni modelli teorici rilevanti sono la teoria dello spazio di lavoro neurale globale, la quale sottolinea la necessità di condivisione dell'informazione tra ampie aree cerebrali e la teoria dell'elaborazione ricorrente che si concentra invece sul feedback proveniente a V1 dalle aree extrastriate. Inoltre, il modello dell’”elaborazione predittiva” descrive la percezione cosciente come il risultato di un processo attivo in cui il cervello crea costantemente previsioni sull’ambiente circostante. Allo stato attuale, la ricerca sui correlati neurali della consapevolezza visiva evidenzia dunque come un network di regioni cerebrali posteriori sia fondamentale per avere esperienze visive coscienti. Inoltre, i segnali di feedback sembrano svolgere un ruolo cruciale, evidenziando le complesse interazioni tra dinamiche neurali e percezione cosciente.The paper aims to present the current evidence regarding how subjective contents of visual awareness are encoded at the neural level. While the neural mechanisms of visual perception are well understood, it remains unclear how visual information becomes part of consciousness. To identify the neural correlates of consciousness (NCC), representing the minimum neural activity for a specific conscious experience, behavioral measures of awareness are related to underlying neural mechanisms, limited to stimuli presented in an experimental context. Through experimental paradigms such as binocular rivalry and visual masking techniques, it is possible to attempt to identify content-specific NCC using neurophysiological measures and neuroimaging techniques. These techniques indeed provide valuable information about the neuroanatomical and functional basis of the examined experience. Although mechanisms underlying attention are often associated with conscious experience, experimental evidence suggests a separation between the two processes. Research on the neural correlates of visual awareness indicates that the activity of a single brain area may not be necessary and sufficient to explain the qualities of conscious contents. Instead, a distributed representation of the visual scene in the primary visual cortex (V1) and ventral visual areas with activation of temporo-parietal regions seems to be necessary. Electrophysiological measures such as Visual Awareness Negativity (VAN) have been correlated with visual awareness, while other indicators appear to be more related to attentional processes. Various theoretical models offer empirical explanations of the emergence of consciousness from brain activity. In the case of visual awareness, some relevant theoretical models include the global neural workspace theory, which emphasizes the need for information sharing among extensive brain areas, and the recurrent processing theory, which focuses on feedback from extrastriate areas to V1. Additionally, the predictive processing model describes conscious perception as the result of an active process in which the brain constantly generates predictions about the surrounding environment. Currently, research on the neural correlates of visual awareness highlights the importance of a network of posterior brain regions for conscious visual experiences. Furthermore, feedback signals appear to play a crucial role, highlighting the complex interactions between neural dynamics and conscious perception