Investigation of Memory Related Cortical Thalamic Circuitry in the Human Brain

This dissertation examined the role of medial prefrontal cortex (mPFC) and the hippocampus (HC) in episodic memory, and provides a novel approach to identify the midline thalamus mediating mPFC-HC interactions in humans. The mPFC and HC are critical to the temporal organization of episodic memory, and these interactions are disrupted in several mental health and neurological disorders. In the first study, I provide evidence that the mPFC is involved in ordinal retrieval, and the HC is active in temporal context retrieval in remembering the order of when events happen. In the second study, I focus on the anatomical basis of the mPFC-HC interactions which is reliant on the midline thalamus. I review in detail the anatomy of the midline thalamus both in location, and connectivity profile with the rest of the brain comparing the extensive anatomical evidence in rodents with the available evidence in monkeys and humans. This section also elaborates on the role of the midline thalamus in memory, stress regulation, wakefulness, and feeding behavior, and how pathological markers along the midline thalamus are a vanguard of several neurological disorders including Alzheimer’s Disease, schizophrenia, depression, and drug addiction. Lastly, I devised a new approach to identify the midline thalamus in humans in vivo using diffusion weighted imaging, capitalizing on known fiber connections gleaned from non-human animals, focusing on connections between the midline thalamus and the mPFC, medial temporal lobe and the nucleus accumbens. The success of this approach is promising for translational imaging. Overall, this dissertation provides new evidence on 1) complementary functional roles of the mPFC and HC in sequence memory, 2) a cross-species anatomical framework for understanding the midline thalamus in humans and neurological disorders, and 3) a new method for non-invasive identification of the midline thalamus in humans in vivo. Thus, this dissertation provides a new fundamental understanding of mPFC-midline thalamic-HC circuit in humans and tools for its non-invasive study in human disease

Flights and Perchings of the BrainMind: A Temporospatial Approach to Psychotherapy

This article introduces a process-oriented approach for improving present moment conceptualization in psychotherapy that is in alignment with neuroscience: the Temporospatial movements of mind (TSMM) model. We elaborate on seven temporal movements that describe the moment-to-moment morphogenesis of emotional feelings and thoughts from inception to maturity. Temporal refers to the passage of time through which feelings and thoughts develop, and electromagnetic activity, that among other responsibilities, bind information across time. Spatial dynamics extend from an undifferentiated to three dimensional experiences of emotional and cognitive processes. Neurophysiologically, spatial refers to structures within the brain and their varying interactions with one another. This article culminates in the development of an atheoretical temporospatial grid that may help clinicians conceptualize where patients are in their cognitive and emotional development to further guide technique

Behavioral and fMRI-based Characterization of Cognitive Processes Supporting Learning and Retrieval of Memory for Words in Young Adults

A novel word is rarely defined explicitly during the first encounter. With repeated exposure, a decontextualized meaning of the word is integrated into semantic memory. With the overarching goal of characterizing the functional neuroanatomy of semantic processing in young adults, we employed a contextual word learning paradigm, creating novel synonyms for common animal/artifact nouns that, along with additional real words, served as stimuli for the lexical-decision based functional MRI (fMRI) experiment. Young adults (n=28) were given two types of word learning training administered in multiple sessions spread out over three days. The first type of training provided perceptual form-only training to pseudoword (PW) stimuli using a PW-detection task. The second type of training assigned the meaning of common artifacts and animals to PWs using multiple sentences to allow contextual meaning acquisition, essentially creating novel synonyms. The underlying goals were twofold: 1) to test, using a behavioral semantic priming paradigm, the hypothesis that novel words acquired in adulthood get integrated into existing semantic networks (discussed in Chapter 2); and 2) to investigate the functional neuroanatomy of semantic processing in young adults, at the single word level, using the newly learned as well as previously known word stimuli as a conduit (discussed in Chapter 3). As outlined in Chapter 2, in addition to the semantic priming test mentioned above, two additional behavioral tests were administered to assess word learning success. The first was a semantic memory test using a two-alternative sentence completion task. Participants demonstrated robust accuracy (~87%) in choosing the appropriate meaning-trained item to complete a novel sentence. Second, an old/new item recognition test was administered using both meaning and form trained stimuli (old) as well as novel foil PWs (new). Participants demonstrated: a) high discriminability between trained and novel PW stimuli. (d-prime=2.72); and b)faster reaction times and higher accuracy for meaning-trained items relative to perceptually-trained items, consistent with prior level-of-processing research. The results from the recognition and semantic memory tests confirmed that subjects could explicitly recognize trained items as well as demonstrate knowledge of the newly acquired synonymous meanings. Finally, using a lexical decision task, a semantic priming test assessed semantic integration using the novel trained items as primes for word targets that had no prior episodic association to the primes. Relative to perceptually trained primes, meaning-trained primes significantly facilitated lexical decision latencies for synonymous word targets. Taken together, the behavioral findings outlined above demonstrate that a contextual approach is effective in facilitating word learning in young adults. Words learned over a few experimental sessions were successfully retained in declarative memory, as demonstrated by behavioral performance in the semantic memory and recognition memory experiments. In addition, relative to perceptually-trained PWs, the newly meaning-trained PWs, when used as primes in a semantic priming test, facilitated lexical decisions for synonymous real words, with which the primes had no prior episodic association. The latter finding confirms our primary behavioral hypothesis that novel words acquired in adulthood are represented similarly, i.e. integrated in the same semantic memory representational network, as common words likely acquired early in the lifetime. Chapter 3 outlines the findings from the fMRI experiment used to investigate the functional neuroanatomy of semantic processing using the newly learned as well as previously known words as stimuli in a lexical decision task. fMRI data were collected using a widely-spaced event-related design, allowing isolation of item-level hemodynamic responses. Two fMRI sessions were administered separated by 2-3 days, the 1st session conducted prior to, and the 2nd session following word-learning training. Using the same items as stimuli in the fMRI sessions conducted before and after behavioral training, facilitated a within-item analysis where each item effectively served as its own control. A set of stringent criteria, outlined below, were established a-priori describing characteristics expected from regions with a role in retrieving/processing meanings at the single word level. We expected a putative semantic processing region to exhibit: a) higher BOLD activity during the 1st fMRI session for real words relative to novel PWs; b) reduced BOLD activity for repeated real words presented in the 2nd fMRI session relative to levels seen in the 1st fMRI session; c) higher BOLD activity for meaning-trained PWs relative to novel PWs; d) higher BOLD activity for meaning-trained PWs relative to perceptually-trained PWs, e) higher BOLD activity for correctly identified meaning-trained PWs (hits) relative to their incorrect counterparts (misses). Given their previously documented associations with semantic processing, we expected to identify regions in left middle temporal gyrus (MTG) and left ventral inferior frontal gyrus (vIFG) to exhibit timecourses consistent with most of the semantic criteria outlined above. Individual ANOVA contrasts, essentially targeting each of the criteria outlined above, were conducted at the voxelwise level. A fixed effects analysis based on 4 correct trial ANOVA contrasts (corresponding to criteria a-d, above) generated 81 regions of interest; and two individual error vs. correct trial ANOVA contrasts generated an additional 16 regions, for a total of 97 study-driven regions. Using region-level ANOVAs and qualitative timecourse examinations, the regions were probed for the presence of the effects outlined in the above criteria. To ensure a comprehensive analysis, additional regions were garnered from prior studies that have used a variety of tasks to target semantic processing. The literature-derived regions were subjected to similar ANOVAs and qualitative timecourse analysis as was conducted on the study-driven regions to examine if the regions exhibited effects outlined in the above criteria. The above analysis resulted in three principal observations. First, we identified regions in the left parahippocamal gyrus (PHG) and left medial superior frontal cortex (mSFC) that, by satisfying essentially all the above criteria, demonstrated a role in semantic memory retrieval for recently acquired and previously known words. Second, despite strong expectations, regions in the left MTG and left vIFG failed to show activity in support of a role in semantic retrieval for the novel words. On the contrary, the profiles seen in the two said regions, namely a ‘word \u3e novel PW’ and a word repetition suppression effect, were consistent with a role in semantic retrieval exclusively for the previously known words. The latter observation suggests that the novel words have yet to undergo adequate consolidation to engage, in addition to PHG and mSFC, canonical semantic regions such as left MTG. Third, despite the potentially crucial distinctions noted in Chapter 3, left lateral/medial parietal regions implicated in episodic memory retrieval exhibited many similar properties as those outlined for PHG and mSFC above during retrieval of newly learned words. Crucially, instead of exhibiting repetition suppression for real words, as observed in PHG/mSFC, the parietal regions showed the opposite effect resembling the episodic ‘old\u3enew’ retrieval success effect. The latter observation argues against a sematic role and in support of an episodic role consistent with previous literature. Taken together, these observations suggest that in addition to the role played by PHG/mSFC supporting semantic memory retrieval for the novel words, the parietal regions are also making significant contributions for memory retrieval of the novel words via complementary episodic processes. Finally, using item-level timecourses derived from the 97 study-driven ROI, clustering algorithms were used to group regions with similar characteristics, with the goal of identifying a cluster corresponding to a putative semantic brain system. A number of clusters were identified containing regions with anatomical and functional correspondence to previously well-characterized systems. For instance, a cluster containing regions in left lateral parietal cortex, precuneus, and superior frontal cortex corresponding to a previously described episodic memory retrieval system (Nelson et al., 2010) was identified. Two additional clusters, corresponding to frontoparietal and cinguloopercular task control systems (Dosenbach et al., 2006, 2007) were also among the identified clusters. However, the clustering analysis did not identify a cluster of regions with semantic properties, such as PHG and mSFC noted above, that could potentially correspond with a semantic brain system. The above outlined findings from the current study, juxtaposed with prior findings from the literature, were interpreted in the following manner. The two regions identified in the current study, i.e. left parahippocampal gyrus and medial superior frontal gyrus, constitute regions that are used for learning new words, and are also recruited during semantic retrieval of previously well-established meanings. In addition, the current results also suggest complementary episodic contributions to the word learning process from regions in left parietal/superior frontal cortex. The latter observation may imply strong episodic contributions to the observed behavioral semantic priming effects. A potential counter argument, i.e. in support of a semantic basis for the priming effects, is the shared recruitment, in a manner consistent with semantics, of PHG/mSFC by both novel and real word stimuli. The left middle temporal gyrus, a region that the task-evoked and neuropsychological literature consistently associates with word-level semantic processing, was not recruited during memory retrieval of novel words, despite robust engagement by previously known word stimuli. Given their association with category-selective semantic deficits, as well as their role in conceptual/perceptual processing in healthy brains, the memory consolidation literature proposes regions in the lateral temporal lobes as potential neocortical loci for consolidated long-term memory. In the current setting, it is likely the case that the novel words have yet to be adequately consolidated to engage left MTG as did the previously known words. Finally, the left vIFG exhibited similar characteristics as the left middle temporal gyrus, in that it was not recruited by the newly meaning trained stimuli, despite showing engagement by previously known words. Given that the region failed to appear in our primary contrasts, even those targeting real word stimuli, and its absence in other prior studies that have used similar lexical decision tasks as the current study, we have a slightly different interpretation for that region. The left vIFG is typically recruited in task settings that require controlled/strategic meaning retrieval, a process that may not be critical for adequate performance of the lexical decision task as employed in the current study. Taken together, these findings suggest that a relatively small amount of word learning training is sufficient to create novel words that, in young adults, behaviorally resemble the semantic characteristics of well-known words. On the other hand, the fMRI findings, particularly the failure of the newly meaning-trained items to engage regions that are canonically responsive to single word meanings (e.g. middle temporal gyrus), may suggest a more protracted timecourse for the functional signature of novel words to resemble that of well-known words. That said, the fMRI findings identified brain regions (left PHG/mSFC) that, consistent with the memory consolidation literature, serve as the functional neuroanatomical “bridge” that connects the novel words to the eventual functional representational destination

Learning to recognize novel words and novel objects

Reading seems as easy and natural as listening. It is still not clear how we acquire this skill, and how visual word identification mechanisms are refined through reading experience. Theoretical models of word recognition describe general principles of skilled reading behaviour. However, these models have been based on averaged data from relatively small samples of skilled readers, mainly English native speakers, and are based on the assumption that skilled reading involves a specialized system of word identification. In this thesis it is proposed that expert reading requires the development and refinement of basic visual processing mechanisms originally employed to identify everyday objects, and then adapted to reading. To test this hypothesis, I carried out three experiments investigating: (i) how L2 visual word recognition changes with growing proficiency; (ii) how novel lexical memories are integrated into the lexicon, i.e., how they interact with previously existing words; and (iii) how sensitivity to the lexicon statistics plays out in the process of learning a novel set of visual stimuli, either in the language and non--language domain

Hippocampus dependent and independent theta-networks of working memory maintenance

Working memory is the ability to briefly maintain and manipulate information beyond its transient availability to our senses. This process of short-term stimulus retention has often been proposed to be anatomically distinct from long-term forms of memory. Although it’s been well established that the medial temporal lobe (MTL) is critical to long-term declarative memory, recent evidence has suggested that MTL regions, such as the hippocampus, may also be involved in the working memory maintenance of configural visual relationships. I investigate this possibility in a series of experiments using Magnetoencephalography to record the cortical oscillatory activity within the theta frequency band of patients with bilateral hippocampal sclerosis and normal controls. The results demonstrate that working memory maintenance of configural-relational information is supported by a theta synchronous network coupling frontal, temporal and occipital visual areas, and furthermore that this theta synchrony is critically dependent on the integrity of the hippocampus. Alternate forms of working memory maintenance, that do not require the relational binding of visual configurations, engage dissociable theta synchronous networks functioning independently of the hippocampus. In closing, I will explore the interactions between long-term and short-term forms of memory and demonstrate that through these interactions, memory performance can effectively be improved

Intracellular mechanisms of cocaine-memory reconsolidation in the basolateral amygdala and dorsal hippocampus

The ability of cocaine-associated environmental contexts to promote relapse in abstinent humans and reinstatement of cocaine-seeking behavior in laboratory animals depends on the formation and maintenance of maladaptive context-response-cocaine associative memories, the latter of which can be disrupted by manipulations that interfere with memory reconsolidation. Memory reconsolidation refers to a protein synthesis-dependent phenomenon whereby memory traces are reincorporated back into long-term memory storage following their retrieval and subsequent destabilization. To elucidate the distinctive roles of the basolateral amygdala (BLA) and dorsal hippocampus (DH) in the reconsolidation of context-response-cocaine memories, Experiments 1-3 evaluated novel molecular mechanisms within each structure that control this phenomenon. Experiment 1 tested the hypothesis that activation of the extracellular signal-regulated kinase (ERK) in the BLA and nucleus accumbens core (NACc - a substrate for Pavlovian cocaine-memory reconsolidation) would critically control instrumental cocaine-memory reconsolidation. To determine this, rats were re-exposed to a context that had previously been used for cocaine self-administration (i.e., cocaine memory-reactivation) and immediately thereafter received bilateral intra-BLA or intra-NACc microinfusions of the ERK inhibitor U0126 or vehicle (VEH) and were subsequently tested for drug context-induced cocaine-seeking behavior (non-reinforced lever responding) ~72 h later. Re-exposure to the cocaine-paired context at test fully reinstated cocaine-seeking behavior, relative to responding in an alternate, extinction context, and post-reactivation U0126 treatment in the BLA, but not the NACc, impaired cocaine-seeking behavior, relative to VEH. This effect was associated with a temporary increase in ERK2, but not ERK1, phosphorylation in the BLA and required explicit reactivation of the target memory trace (i.e., did not similarly manifest when U0126 was administered after exposure to an unpaired context), suggesting that ERK in the BLA plays a critical role in restabilizing contextual cocaine-related memories. Next, Experiment 2 evaluated the hypothesis that the transcription factor (TF) nuclear factor-&kappab (NF-&kappaB) would also critically mediate instrumental cocaine-memory reconsolidation in the BLA. Remarkably, the NF-&kappab inhibitor, sulfasalazine (SSZ), administered bilaterally into the BLA following cocaine-memory reactivation, did not significantly alter subsequent cocaine-seeking behavior, relative to VEH, despite producing an observable trend for an enhancement in this behavior. Future studies will be needed to further examine this relationship, but the present findings may suggest that NF-&kappaB TFs acts as negative regulators of cocaine-memory reconsolidation. Finally, Experiment 3 tested the hypothesis that members of the Src family of tyrosine kinases (SFKs) are obligatory for instrumental cocaine-memory reconsolidation. Consistent with our hypothesis, PP2, a nonspecific inhibitor of SFKs, administered bilaterally into the DH after cocaine-memory reactivation, attenuated subsequent drug-context induced motivation for cocaine, relative to VEH, in a memory reactivation-dependent manner. This effect was associated with a preferential disruption of SFK-mediated phosphorylation of the NR2a N-methyl-D-aspartate receptor (NMDAR) subunit. Together, these findings begin to illuminate how the BLA and DH may subserve the long-term stability of maladaptive cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior.Doctor of Philosoph

Reconsidering Visual Statistical Learning: Effects of Attention, Assessment, and Associability

Improving the ease of learning has been a centuries-long pursuit. One tantalizing possibility is that there may be conditions under which learning occurs “automatically” and implicitly. Such a learning process would have profound impacts on pedagogy and our understanding of human development. This type of learning process has, ostensibly, been studied as “statistical learning” over the past 25 years. In this thesis, I propose that although genuine forms of automatic and implicit learning do exist, the standard paradigm for studying visual statistical learning, in adults, does not isolate an automatic and implicit learning process. Additionally, I show that some of the evidence for implicit visual statistical learning, which appeared to be strong, is in fact the result of experimental confounds in response time measures. Finally, I show that stimulus choice significantly affects visual statistical learning, suggesting links with traditionally studied associative learning. I motivate this proposal with an overview of the field of statistical learning and what distinguishes it from other forms of learning (Chapter 1). I support this proposal with evidence from four sets of experiments which investigate the: effects of automaticity and attention (Chapter 2), indirect assessment of visual statistical learning (Chapter 3), and the associability of arbitrary stimuli (Chapter 4). I conclude with a summary of our findings and how they integrate into the broader study of learning processes, along with open questions for future investigation (Chapter 5). To preview our four major findings, we find that: (1) when participants attend to stimulus motion, increasing the amount of exposure does not improve learning of visual sequence regularities, (2) the attentional state of participants significantly affects how well they learn statistical regularities, (3) important evidence in the literature for an implicit statistical learning process – response time facilitation within learned sequences – actually appears to arise from a methodological confound, and (4) stimulus associability is affected by stimulus choice, with faces associated more rapidly than arbitrary fractals. Collectively, these data suggest a reconsideration of visual statistical learning from an automatic, implicit learning process to a more attention-dependent and volitional learning process

Learning to Dream, Dreaming to Learn

The importance of sleep for healthy brain function is widely acknowledged. However, it remains mysterious how the sleeping brain, disconnected from the outside world and plunged into the fantastic experiences of dreams, is actively learning. A main feature of dreams is the generation of new realistic sensory experiences in absence of external input, from the combination of diverse memory elements. How do cortical networks host the generation of these sensory experiences during sleep? What function could these generated experiences serve? In this thesis, we attempt to answer these questions using an original, computational approach inspired by modern artificial intelligence. In light of existing cognitive theories and experimental data, we suggest that cortical networks implement a generative model of the sensorium that is systematically optimized during wakefulness and sleep states. By performing network simulations on datasets of natural images, our results not only propose potential mechanisms for dream generation during sleep states, but suggest that dreaming is an essential feature for learning semantic representations throughout mammalian development

A multicomponential examination of tennis players’ emotional responses to music

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.The principal aim of this research programme was to examine multiple components of competitive tennis players’ emotional responses to pre-performance music. To this end, four objectives were defined: First, to develop a grounded theory (Glaser & Strauss, 1967) of players’ use of music to manipulate emotional state; second, to examine the impact of altering music tempo and intensity on players’ affective and behavioural responses; third, to identify neural origins for these phenomena; and fourth, to elucidate the role of motoneuron excitability in behavioural responses observed. These objectives were realised in four interrelated studies. First, 14 players provided quantitative and qualitative interview, questionnaire, and diary data to detail their use of personally emotive music; a grounded theory and associated model were consequently developed to facilitate future research and practice. Participants used music to attain five broad emotional states, including psyched-up; this was associated with faster tempi and louder intensities (volumes). Study 2 was conceived to examine the effects of manipulating these variables on 54 players’ affective and behavioural states, using measures based on Russell’s (1980) affective circumplex and reaction times (RTs). Faster tempi elicited higher valence and arousal, loud intensity yielded higher arousal and shorter RTs; and higher arousal was associated with shorter RTs. Functional magnetic resonance imaging was utilised in Study 3 to identify neural bases for 12 participants’ emotional responses to the same music manipulations; emotion-processing, visuomotor and sensorimotor structures were activated under high-arousal conditions. Transcranial magnetic stimulation and electromyography were used in Study 4 to investigate changes in 10 participants’ corticospinal excitability as a result of listening to purposively selected music; optimised music elicited higher arousal and reduced corticospinal response latencies. The foremost contribution of this thesis is to show that music variables may be carefully selected and/or manipulated to maximise performance-facilitating emotional responses to music in tennis

Mechanisms of sleep-associated memory consolidation and next-day learning

Sleep is linked to overnight memory consolidation and next-day learning. However, it is unclear which mechanisms of sleep support these memory processes. The Active Systems Consolidation model postulates that during sleep, newly formed hippocampus-dependent memories are reactivated and transformed into stable representations within neocortex. This transformation may, in turn, refresh new learning capacity within hippocampus. With a basis in these assumptions, the present thesis aimed to investigate how sleep facilitates offline consolidation and whether sleep-associated consolidation might contribute to learning the following day. Firstly, a targeted memory reactivation paradigm investigated the oscillatory signatures of reactivation during sleep elicited by verbal and non-verbal memory cues. Increases in theta and spindle power were linked to memory reactivation and stabilization during sleep, and furthermore, verbal cues evoked stronger spindle-mediated memory processes as compared to non-verbal memory cues. Secondly, three experiments investigated the benefits of sleeping before and after learning as compared to staying awake, either overnight or during the day. The results suggested that sleep benefits memory consolidation, and that losing sleep disrupts a neural signature of successful learning, namely, beta desynchrony. However, no benefits of sleeping prior to learning were observed when compared to daytime wakefulness. Addressing the novel hypothesis of a potential relationship between sleep-associated consolidation and next-day learning, three experiments consistently found no evidence to support this hypothesis. Surprisingly, an association was reported between forgetting during daytime wakefulness and subsequent learning of similar materials. Overall, this thesis provides insights into how sleep supports consolidation and raises novel questions about which processes during both sleep and wake may support new memory formation