CNTRICS Final Task Selection: Long-term Memory

Long-term memory (LTM) is a multifactorial construct, composed of different stages of information processing and different cognitive operations that are mediated by distinct neural systems, some of which may be more responsible for the marked memory problems that limit the daily function of individuals with schizophrenia. From the outset of the CNTRICS initiative, this multidimensionality was appreciated, and an effort was made to identify the specific memory constructs and task paradigms that hold the most promise for immediate translational development. During the second CNTRICS meeting, the LTM group identified item encoding and retrieval and relational encoding and retrieval as key constructs. This article describes the process that the LTM group went through in the third and final CNTRICS meeting to select nominated tasks within the 2 LTM constructs and within a reinforcement learning construct that were judged most promising for immediate development. This discussion is followed by each nominating authors' description of their selected task paradigm, ending with some thoughts about future directions.Psycholog

Functional imaging of response selection

The functions of the prefrontal cortex remain controversial. Electrophysio- logical and lesion studies in monkeys have emphasised a role in working memory. In contrast, human functional neuroimaging studies and neuropsychology have emphasised a role in executive processes and volition. An alternative interpretation of the role of the prefrontal cortex is proposed in this thesis: that the prefrontal cortex mediates the attentional selection of sensory, mnemonic and motor representations in non-prefrontal cortex. This hypothesis is tested in a series of functional imaging experiments. In the first two experiments (chapters 4 and 5), event-related functional magnetic resonance imaging (fMRI) was used to re-examine the role of the prefrontal cortex in spatial and spatio-temporal working memory. Maintenance of information in memory was associated with activation of posterior prefrontal cortex (area 8). In contrast, the selection of an item from several remembered items was associated with activation of the middle and anterior parts of the prefrontal cortex (including area 46). To test the generalisation of 'selection' as a function of prefrontal cortex, experiment three (chapter 6) required subjects to select either a finger to move, or a colour from a multicolour display. Free selection was associated with activation of the prefrontal cortex (area 46) bilaterally, regardless of sensory or motor modality. The selection of voluntary actions has been proposed to depend on top-down modulation of motor regions by prefrontal cortex. The fourth and fifth experiments used structural equation modelling of fMRI time -series to measure the effective connectivity among prefrontal, premotor and parietal cortex. In young (chapter 7) and old (chapter 8) normal subjects, attention to action specifically enhanced coupling between prefrontal and premotor regions. This effect was not seen in patients with Parkinson's disease (chapter 8). Lastly, positron emission tomography was used to study planning in the Tower of London task, a common clinical measure of prefrontal function. Several variants of the task were developed, to distinguish the neural basis of the task's multiple cognitive components (chapter 9). The prefrontal cortex was activated in association with generation, selection or memory for moves, rather than planning towards a specified goal. The results support a generalised role in attentional selection of neuronal representations, whether stimuli, actions, or remembered items. The hypothesised attentional selection of responses is consistent with the activation of prefrontal cortex in working memory tasks and during attention to voluntary action. This role is compatible with the neurophysiological properties of individual neurons in the prefrontal cortex and the results of neuroimaging and lesion studies

Neurobiological mechanisms of hallucinations in schizophrenia

All perception is a construct of the brain. Yet occasionally, sensory constructions emerge without origin in the physical world and are experienced as hallucinations. Hallucinations occur transdiagnostically, cross-culturally, and in all sensory modalities. They are common in people with schizophrenia, presenting in 60-80% of patients. Despite over 20 years of active neuroimaging research on hallucinations, the neural systems supporting these anomalous perceptual experiences remain disputed. This dissertation investigates the neurobiology of hallucinations, integrating research across structural and functional magnetic resonance imaging (MRI) to elucidate how hallucinations, chiefly in the context of schizophrenia, are supported by the brain, drawing on MRI indices of neurodevelopment. I introduce the phenomenon of hallucinations and motivate the utility of MRI for studying hallucinations. Considering their prevalence in other medical conditions, I conduct a meta-analysis and systematic review of the structural brain basis of hallucinations across diagnoses, primarily schizophrenia spectrum disorders and Parkinson’s disease. This illustrated distinct neuroanatomical organizations of grey matter associated with hallucinations that occur in neurodevelopmental compared to neurodegenerative disorders, which I hypothesise constitute at least two distinct mechanisms. Focussing on the neurodevelopmental mechanism characterized by fronto-temporal and insular grey matter reductions, I turn to the contribution of cortical sulcation, a product of second and third trimester neurodevelopmental processes, which has been robustly implicated in schizophrenia pathology, and, more recently, in hallucinations. Sulcal patterns derived from structural MRI provide a proxy in adulthood for early brain development. I studied two independent datasets of patients with schizophrenia who underwent clinical assessment and 3T MRI from the United Kingdom and Shanghai, China, stratified into those with and without hallucinations, and healthy controls from Shanghai. I first replicate the finding that left hemisphere paracingulate sulcus (PCS) length is reduced in patients who experience hallucinations, then demonstrate similar associations for superior temporal sulcus depth. Length and depth alterations occurred with focal deviations in sulcal geometry. The interindividual and interhemispheric variability of the PCS necessitated the development of semi-automated methods to characterize its morphology and validation to a manual protocol. I used structural covariance networks of the local gyrification index to investigate how specific sulcal deviations relate to global neurodevelopmental coordination, demonstrating that hallucinations correspond to increased covariance within and between salience and auditory networks. Hypothesizing structure-function relationships, I analyse resting-state functional MRI data from the same datasets described, finding significant interactions between PCS length and hallucinations status, but no main effects. There were no effects of hallucination status on salience and auditory network connectivity or in graph theoretical measures of connectivity, suggesting that resting-state connectivity is not a trait marker for hallucinations. Together, the discovery of neurodevelopmental alterations contributing to hallucinations provides mechanistic insight into the pathological consequences of prenatal origins. The interaction of sulcal alterations and hallucination status are associated with connectivity, which may have a role in the pathophysiology of hallucinations. I provide clear predictions and recommendations for future research.Gates Cambridge Scholarshi

Verbal monitoring in production and perception : a cognitive neuroscience approach

The goal of this dissertation is to investigate the process of verbal monitoring. Specifically, this thesis investigates whether internal and external monitoring proceeds via the same, perception-based process, as proposed by the perceptual loop theory. We compare verbal internal and external monitoring with the use of eye-tracking, fMRI and Parkinson patient data. The data obtained suggest that verbal monitoring is not perception based, and that is a domain general process. We therefore propose the improvement of current monitoring models by describing a domain general monitoring mechanism for internal monitoring and external monitoring, by which conflict is resolved in a process-independent manner

Obesity is associated with insufficient behavioral adaptation

Obesity is one of the major health concerns nowadays according to the World Health Organisation (WHO global status report on noncommunicable diseases 2010). Thus, there is an urgent need for understanding obesity-associated alterations in food-related and general cognition and their underlying structural and functional correlates within the central nervous system (CNS). Neuroscientific research of the past decade has mainly focussed on obesity-related differences within homeostatic and hedonic processing of food stimuli. Therein, alterations during anticipation and consumption of food-reward stimuli in obese compared with lean subjects have been highlighted. This points at an altered adaptation of eating behavior in obese individuals. This thesis investigates if adaptation of behavior is attenuated in obese compared to lean individuals in learning-related processes beyond the food domain. In five consecutive experimental studies, we show that obese participants reveal reduced adaptation of behavior within and outside the food context. With the help of MRI, we relate these behavioral findings to alterations in structure and function of the fronto-striatal dopaminergic system in obesity. In more detail, reduced behavioral adaptation seems to be associated with attenuated utilization of negative prediction errors in obese individuals. Within the brain, this relates to reduced functional coupling between subcortical dopaminergic target regions (ventral striatum) and executive cortical structures (supplementary motor area) in obesity, as revealed by fMRI analysis

Sensorimotor Modulations by Cognitive Processes During Accurate Speech Discrimination: An EEG Investigation of Dorsal Stream Processing

Internal models mediate the transmission of information between anterior and posterior regions of the dorsal stream in support of speech perception, though it remains unclear how this mechanism responds to cognitive processes in service of task demands. The purpose of the current study was to identify the influences of attention and working memory on sensorimotor activity across the dorsal stream during speech discrimination, with set size and signal clarity employed to modulate stimulus predictability and the time course of increased task demands, respectively. Independent Component Analysis of 64–channel EEG data identified bilateral sensorimotor mu and auditory alpha components from a cohort of 42 participants, indexing activity from anterior (mu) and posterior (auditory) aspects of the dorsal stream. Time frequency (ERSP) analysis evaluated task-related changes in focal activation patterns with phase coherence measures employed to track patterns of information flow across the dorsal stream. ERSP decomposition of mu clusters revealed event-related desynchronization (ERD) in beta and alpha bands, which were interpreted as evidence of forward (beta) and inverse (alpha) internal modeling across the time course of perception events. Stronger pre-stimulus mu alpha ERD in small set discrimination tasks was interpreted as more efficient attentional allocation due to the reduced sensory search space enabled by predictable stimuli. Mu-alpha and mu-beta ERD in peri- and post-stimulus periods were interpreted within the framework of Analysis by Synthesis as evidence of working memory activity for stimulus processing and maintenance, with weaker activity in degraded conditions suggesting that covert rehearsal mechanisms are sensitive to the quality of the stimulus being retained in working memory. Similar ERSP patterns across conditions despite the differences in stimulus predictability and clarity, suggest that subjects may have adapted to tasks. In light of this, future studies of sensorimotor processing should consider the ecological validity of the tasks employed, as well as the larger cognitive environment in which tasks are performed. The absence of interpretable patterns of mu-auditory coherence modulation across the time course of speech discrimination highlights the need for more sensitive analyses to probe dorsal stream connectivity

Do informal caregivers of people with dementia mirror the cognitive deficits of their demented patients?:A pilot study

Recent research suggests that informal caregivers of people with dementia (ICs) experience more cognitive deficits than noncaregivers. The reason for this is not yet clear. Objective: to test the hypothesis that ICs ‘mirror' the cognitive deficits of the demented people they care for. Participants and methods: 105 adult ICs were asked to complete three neuropsychological tests: letter fluency, category fluency, and the logical memory test from the WMS-III. The ICs were grouped according to the diagnosis of their demented patients. One-sample ttests were conducted to investigate if the standardized mean scores (t-scores) of the ICs were different from normative data. A Bonferroni correction was used to correct for multiple comparisons. Results: 82 ICs cared for people with Alzheimer's dementia and 23 ICs cared for people with vascular dementia. Mean letter fluency score of the ICs of people with Alzheimer's dementia was significantly lower than the normative mean letter fluency score, p = .002. The other tests yielded no significant results. Conclusion: our data shows that ICs of Alzheimer patients have cognitive deficits on the letter fluency test. This test primarily measures executive functioning and it has been found to be sensitive to mild cognitive impairment in recent research. Our data tentatively suggests that ICs who care for Alzheimer patients also show signs of cognitive impairment but that it is too early to tell if this is cause for concern or not

Human aging, dopamine, and cognition : molecular and functional imaging of executive functions and implicit learning

Age-related deficits are legion in task switching, updating of information in working memory (WM) and inhibiting irrelevant information, collectively referred to as executive functions. Executive functions are tightly coupled to the dopaminergic system, and marked dopamine (DA) losses are observed across adulthood and aging. Several human molecular imaging studies have sought confirmation for the hypothesis that age-related DA losses are associated with deficits in executive functions in older adults. Study I extends this line of research by investigating the association between caudate DA D1 receptor density and functional network connectivity in younger (20-30 years) and older adults (65-75 years) using positron emission tomography and functional magnetic resonance imaging (fMRI). In line with the notion that striatal DA is a critical modulator in cortico-striato-cortical pathways, caudate D1 receptor density was significantly associated with fronto-parietal connectivity in functional brain networks related to executive functioning, and there were marked age-related reductions in DA D1 binding potential. These results show that age-related losses of caudate D1 receptors may contribute to reduced functional-network integrity in older adults. Study II examined age differences in D1 receptor density in several striatal and cortical regions of interest. On average, D1 receptor densities were reduced by around 20 % for older compared to younger adults. Most interestingly, correlations between striatal and cortical receptor densities were reduced in older compared to younger adults, suggesting that dopaminergic losses in striatum and cortex occur relatively independently. Moreover, reduced correlations between striatal and cortical receptor densities were related to slower cognitive interference resolution in older adults. This pattern suggests that an imbalance in dopaminergic regulation between striatum and cortex may contribute to older adults’ deficits in executive functions. Implicit learning remains relatively spared in older adults despite strong associations to striatal functions and DA. This fact presents a paradox for the hypothesis that age- related DA losses mediate cognitive decline in aging. Study III and IV explore possible compensatory mechanisms, which may contribute to preserved implicit learning among older adults. Study III showed that increases in striatal fMRI activations during implicit sequence learning were accompanied by decreasing activation of the right medial temporal lobe (MTL) in younger adults. Older adults, however, relied on both striatum and right MTL during task performance. This pattern suggests that the MTL is not necessary for implicit learning in younger adults, but serves compensatory purposes in old age. Study IV used a dual-task design during fMRI acquisition in which a secondary task, designed to tax the MTL, was performed concurrent with an implicit sequence-learning task comparable to that used in Study III. Consistent with the interpretation of the data from Study III, the secondary task disrupted learning in older, but not younger adults. Moreover, differential effects of the secondary task on learning in younger and older adults were observed in activation patterns for right MTL. Collectively, the four studies provide novel insights into the mechanisms by which dopaminergic losses in aging contribute to deficits in executive functions, and suggest compensatory processes, which may account for the relative sparing of implicit learning in old age

Event-related potentials and cognition in Parkinson's disease: An integrative review

Cognitive impairment is a common non-motor symptom of Parkinson’s disease (PD), but the nature of cognitive changes varies considerably between individuals. According to the dual-syndrome hypothesis, one cluster of patients is characterized by deficits in executive function that may be related to fronto-striatal dysfunction. Other patients primarily show non-frontal cognitive impairments that progress rapidly to PD dementia (PDD). We provide a comprehensive review of event-related potential (ERP) studies to identify ERP measures substantiating the heterogeneity of cognitive impairment in PD. Our review revealed evidence for P3b and mismatch-negativity alterations in PDD, but not in non-demented PD, indicating that alterations of these ERPs constitute electrophysiological markers for PDD. In contrast, ERP correlates of executive functions, such as NoGo-P3, N2, and error(-related) negativity (Ne/ERN), appear to be attenuated in non-demented PD patients in a dopamine-dependent manner. Hence, ERP measures confirm and yield distinct electrophysiological markers for the heterogeneity of cognitive impairment in PD. We discuss limitations and open questions of the ERP approach and provide directions and predictions for future ERP research