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1.  Contributions of Feature Binding During Encoding and Functional Connectivity of the Medial Temporal Lobe Structures to Episodic Memory Deficits Across the Prodromal and First-Episode Phases of Schizophrenia 
Patients with and at risk for psychosis may have difficulty using associative strategies to facilitate episodic memory encoding and recall. In parallel studies, patients with first-episode schizophrenia (n = 27) and high psychosis risk (n = 28) compared with control participants (n = 22 and n = 20, respectively) underwent functional MRI during a remember-know memory task. Psychophysiological interaction analyses, using medial temporal lobe (MTL) structures as regions of interest, were conducted to measure functional connectivity patterns supporting successful episodic memory. During encoding, patients with first-episode schizophrenia demonstrated reduced functional coupling between MTL regions and regions involved in stimulus representations, stimulus selection, and cognitive control. Relative to control participants and patients with high psychosis risk who did not convert to psychosis, patients with high psychosis risk who later converted to psychosis also demonstrated reduced connectivity between MTL regions and auditory-verbal and visual-association regions. These results suggest that episodic memory deficits in schizophrenia are related to inefficient recruitment of cortical connections involved in associative memory formation; such deficits precede the onset of psychosis among those individuals at high clinical risk.
PMCID: PMC4349206  PMID: 25750836
psychotic disorders; memory; schizophrenia; neuroimaging; functional imaging
2.  Evidence for Corticostriatal Dysfunction During Cognitive Skill Learning in Adolescent Siblings of Patients With Childhood-Onset Schizophrenia 
Schizophrenia Bulletin  2013;40(5):1030-1039.
Patients with schizophrenia perform poorly on cognitive skill learning tasks. This study is the first to investigate the neural basis of impairment in cognitive skill learning in first-degree adolescent relatives of patients with schizophrenia. We used functional magnetic resonance imaging to compare activation in 16 adolescent siblings of patients with childhood-onset schizophrenia (COS) and 45 adolescent controls to determine whether impaired cognitive skill learning in individuals with genetic risk for schizophrenia was associated with specific patterns of neural activation. The siblings of patients with COS were severely impaired on the Weather Prediction Task (WPT) and showed a relative deactivation in frontal regions and in the striatum after extensive training on the WPT compared with controls. These differences were not accounted for by performance differences in the 2 groups. The results suggest that corticostriatal dysfunction may be part of the liability for schizophrenia.
PMCID: PMC4133665  PMID: 24162516
cognitive skill learning; striatal dysfunction; genetic risk; fMRI
3.  Value-based modulation of memory encoding involves strategic engagement of fronto-temporal semantic processing regions 
A number of prior fMRI studies have focused on the ways in which the midbrain dopaminergic reward system co-activates with hippocampus to potentiate memory for valuable items. However, another means by which people could selectively remember more valuable to-be-remembered items is to be selective in their use of effective but effortful encoding strategies. To broadly examine the neural mechanisms of value on subsequent memory, we used fMRI to examine how differences in brain activity at encoding as a function of value relate to subsequent free recall for words. Each word was preceded by an arbitrarily assigned point value, and participants went through multiple study-test cycles with feedback on their point total at the end of each list, allowing for sculpting of cognitive strategies. We examined the correlation between value-related modulation of brain activity and participants’ selectivity index, a measure of how close participants were to their optimal point total given the number of items recalled. Greater selectivity scores were associated with greater differences in activation of semantic processing regions, including left inferior frontal gyrus and left posterior lateral temporal cortex, during encoding of high-value words relative to low-value words. Although we also observed value-related modulation within midbrain and ventral striatal reward regions, our fronto-temporal findings suggest that strategic engagement of deep semantic processing may be an important mechanism for selectively encoding valuable items.
PMCID: PMC4074434  PMID: 24683066
value; memory; selective encoding; reward; metacognitive control; functional magnetic resonance imaging (fMRI)
4.  High-resolution 7T fMRI of Human Hippocampal Subfields during Associative Learning 
Journal of cognitive neuroscience  2014;27(6):1194-1206.
Examining the function of individual human hippocampal subfields remains challenging due to their small sizes and convoluted structures. Previous human functional magnetic resonance (fMRI) studies at 3 Tesla (T) have successfully detected differences in activation between hippocampal cornu ammonis (CA) field CA1, combined CA2, 3 and dentate gyrus (DG) region (CA23DG), and the subiculum during associative memory tasks. In this study we investigated hippocampal subfield activity in healthy participants using an associative memory paradigm during high-resolution functional magnetic resonance imaging (fMRI) scanning at 7T. We were able to localize fMRI activity to anterior CA2 and CA3 during learning, and to the posterior CA2 field, the CA1, and the posterior subiculum during retrieval of novel associations. These results provide insight into more specific human hippocampal subfield functions underlying learning and memory and a unique opportunity for future investigations of hippocampal subfield function in healthy individuals as well as those suffering from neurodegenerative diseases.
PMCID: PMC4417053  PMID: 25514656
Hippocampus; memory; fMRI; MRI; high-resolution imaging
5.  Cognitive correlates of gray matter abnormalities in adolescent siblings of patients with childhood-onset schizophrenia 
Schizophrenia research  2014;161(0):345-350.
Patients with childhood onset schizophrenia (COS) display widespread gray matter (GM) structural brain abnormalities. Healthy siblings of COS patients share some of these structural abnormalities, suggesting that GM abnormalities are endophenotypes for schizophrenia. Another possible endophenotype for schizophrenia that has been relatively unexplored is corticostriatal dysfunction. The corticostriatal system plays an important role in skill learning. Our previous studies have demonstrated corticostriatal dysfunction in COS siblings with a profound skill learning deficit and abnormal pattern of brain activation during skill learning. This study investigated whether structural abnormalities measured using volumetric brain morphometry (VBM) were present in siblings of COS patients and whether these were related to deficits in cognitive skill learning. Results revealed smaller GM volume in COS siblings relative to controls in a number of regions, including occipital, parietal, and subcortical regions including the striatum, and greater GM volume relative to controls in several subcortical regions. Volume in the right superior frontal gyrus and cerebellum were related to performance differences between groups on the weather prediction task, a measure of cognitive skill learning. Our results support the idea that corticostriatal and cerebellar impairment in unaffected siblings of COS patients are behaviorally relevant and may reflect genetic risk for schizophrenia.
PMCID: PMC4405249  PMID: 25541139
Structural abnormalities; Striatal dysfunction; Cognitive skill learning; Schizophrenia; VBM
6.  Impaired automatization of a cognitive skill in first-degree relatives of patients with schizophrenia 
Psychiatry research  2013;215(2):294-299.
We studied healthy, first-degree relatives of patients with schizophrenia to test the hypothesis that deficits in cognitive skill learning are associated with genetic liability to schizophrenia. Using the Weather Prediction Task (WPT), 23 healthy controls and 10 adult first-degree Relatives Of Schizophrenia (ROS) patients were examined to determine the extent to which cognitive skill learning was automated using a dual-task paradigm to detect subtle impairments in skill learning. Automatization of a skill is the ability to execute a task without the demand for executive control and effortful behavior and is a skill in which schizophrenia patients possess a deficit. ROS patients did not differ from healthy controls in accuracy or reaction time on the WPT either during early or late training on the single-task trials. In contrast, the healthy control and ROS groups were differentially affected during the dual-task trials. Our results demonstrate that the ROS group did not automate the task as well as controls and continued to rely on controlled processing even after extensive practice. This suggests that adult ROS patients may engage in compensatory strategies to achieve normal levels of performance and support the hypothesis that impaired cognitive skill learning is associated with genetic risk for schizophrenia.
PMCID: PMC4191851  PMID: 24359887
Automatization; Schizophrenia; Skill learning; Genetic liability
7.  Top-down modulation of hippocampal encoding activity as measured by high-resolution functional MRI 
Neuropsychologia  2013;51(10):10.1016/j.neuropsychologia.2013.06.026.
Memory formation is known to be critically dependent upon the medial temporal lobe (MTL). Despite this well-characterized role, it remains unclear whether and how MTL encoding processes are affected by top-down goal states. Here, we examined the manner in which task demands at encoding affect MTL activity and its relation to subsequent memory performance. Participants were scanned using high-resolution neuroimaging of the MTL while engaging in two incidental encoding tasks: one that directed participants’ attention to stimulus distinctiveness, and the other requiring evaluation of similarities across stimuli. We hypothesized that attending to distinctiveness would lead to the formation of more detailed memories and would more effectively engage the hippocampal circuit than attending to similarity. In line with our hypotheses, higher rates of subsequent recollection were observed for stimuli studied under the Distinctiveness than Similarity task. Critically, within the hippocampus, CA1 and the subiculum demonstrated an interaction between memory performance and task such that a significant subsequent memory effect was found only when task goals required attention to stimulus distinctiveness. To this end, robust engagement of the hippocampal circuit may underlie the observed behavioral benefits of attending to distinctiveness. Taken together, these findings advance understanding of the effects of top-down intentional information on successful memory formation across subregions of the MTL.
PMCID: PMC3829781  PMID: 23838003
medial temporal lobe; hippocampus; functional MRI; memory; encoding; goal states
8.  Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area 
The New England journal of medicine  2012;366(6):502-510.
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).
Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.
Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.)
PMCID: PMC3447081  PMID: 22316444
9.  Dissociations within Human Hippocampal Subregions during Encoding and Retrieval of Spatial Information 
Hippocampus  2010;21(7):694-701.
Although the hippocampus is critical for the formation and retrieval of spatial memories, it is unclear how subregions are differentially involved in these processes. Previous high-resolution functional magnetic resonance imaging (fMRI) studies have shown that CA2, CA3, and dentate gyrus (CA23DG) regions support the encoding of novel associations, while the subicular cortices support the retrieval of these learned associations. Whether these subregions are employed in humans during encoding and retrieval of spatial information has yet to be explored. Using high-resolution fMRI (1.6 mm × 1.6 mm in-plane), we found that activity within the right CA23DG increased during encoding compared to retrieval. Conversely, right subicular activity increased during retrieval compared to encoding of spatial associations. These results are consistent with previous studies illustrating dissociations within human hippocampal subregions and further suggest these regions are similarly involved during the encoding and retrieval of spatial information.
PMCID: PMC3026858  PMID: 20882543
hippocampus; CA3; subiculum; fMRI; encoding; retrieval; spatial learning
10.  Multimodal Cuing of Autobiographical Memory in Semantic Dementia 
Neuropsychology  2011;25(1):98-104.
Individuals with semantic dementia (SD) have impaired autobiographical memory (AM), but the extent of the impairment has been controversial. According to one report (Westmacott et al., 2001), patient performance was better when visual cues were used instead of verbal cues; however, the visual cues used in that study (family photographs) provided more retrieval support than do the word cues that are typically used in AM studies. In the present study, we sought to disentangle the effects of retrieval support and cue modality.
We cued AMs of 5 SD patients and 5 controls with words, simple pictures, and odors. Memories were elicited from childhood, early adulthood, and recent adulthood; they were scored for level of detail and episodic specificity.
The patients were impaired across all time periods and stimulus modalities. Within the patient group, words and pictures were equally effective as cues (Friedman test; χ2 = 0.25, p = 0.61), whereas odors were less effective than both words and pictures (for words vs. odors, χ2 = 7.83, p = 0.005; for pictures vs. odors, χ2 = 6.18, p = 0.01). There was no evidence of a temporal gradient in either group (for SD patients, χ2 = 0.24, p = 0.89; for controls, χ2 < 2.07, p = 0.35).
Once the effect of retrieval support is equated across stimulus modalities, there is no evidence for an advantage of visual cues over verbal cues. The greater impairment for olfactory cues presumably reflects degeneration of anterior temporal regions that support olfactory memory.
PMCID: PMC3058931  PMID: 21090900
11.  Decoding Continuous Variables from Neuroimaging Data: Basic and Clinical Applications 
The application of statistical machine learning techniques to neuroimaging data has allowed researchers to decode the cognitive and disease states of participants. The majority of studies using these techniques have focused on pattern classification to decode the type of object a participant is viewing, the type of cognitive task a participant is completing, or the disease state of a participant's brain. However, an emerging body of literature is extending these classification studies to the decoding of values of continuous variables (such as age, cognitive characteristics, or neuropsychological state) using high-dimensional regression methods. This review details the methods used in such analyses and describes recent results. We provide specific examples of studies which have used this approach to answer novel questions about age and cognitive and disease states. We conclude that while there is still much to learn about these methods, they provide useful information about the relationship between neural activity and age, cognitive state, and disease state, which could not have been obtained using traditional univariate analytical methods.
PMCID: PMC3118657  PMID: 21720520
predictive analysis; fMRI; high-dimensional regression; multivariate decoding; machine learning
12.  A unique adolescent response to reward prediction errors 
Nature neuroscience  2010;13(6):669-671.
Previous work has demonstrated that human adolescents may be hypersensitive to rewards; it is unknown which aspect of reward processing this reflects. We separated decision value and prediction error signals and found that neural prediction error signals in the striatum peaked in adolescence, whereas neural decision value signals varied depending upon how value was modeled. This suggests that one contributor to adolescent reward-seeking may be heightened dopaminergic prediction error responsivity.
PMCID: PMC2876211  PMID: 20473290
13.  Human Hippocampal CA1 Involvement during Allocentric Encoding of Spatial Information 
A central component of our ability to navigate an environment is the formation of a memory representation that is allocentric and thus independent of our starting point within that environment. Computational models and rodent electrophysiological recordings suggest a critical role for the CA1 subregion of the hippocampus in this type of coding; however, the hippocampal neural basis of spatial learning in humans remains unclear. We studied subjects learning virtual environments using high-resolution functional magnetic resonance imaging (1.6 mm × 1.6 mm in-plane) and computational unfolding to better visualize substructural changes in neural activity in the hippocampus. We show that the right posterior CA1 subregion is active and positively correlated with performance when subjects learn a spatial environment independent of starting point and direction. Altogether, our results demonstrate that the CA1 subregion is involved in our ability to learn a map-like representation of an environment.
PMCID: PMC2873654  PMID: 19710304
14.  Decoding Developmental Differences and Individual Variability in Response Inhibition Through Predictive Analyses Across Individuals 
Response inhibition is thought to improve throughout childhood and into adulthood. Despite the relationship between age and the ability to stop ongoing behavior, questions remain regarding whether these age-related changes reflect improvements in response inhibition or in other factors that contribute to response performance variability. Functional neuroimaging data shows age-related changes in neural activity during response inhibition. While traditional methods of exploring neuroimaging data are limited to determining correlational relationships, newer methods can determine predictability and can begin to answer these questions. Therefore, the goal of the current study was to determine which aspects of neural function predict individual differences in age, inhibitory function, response speed, and response time variability. We administered a stop-signal task requiring rapid inhibition of ongoing motor responses to healthy participants aged 9–30. We conducted a standard analysis using GLM and a predictive analysis using high-dimensional regression methods. During successful response inhibition we found regions typically involved in motor control, such as the ACC and striatum, that were correlated with either age, response inhibition (as indexed by stop-signal reaction time; SSRT), response speed, or response time variability. However, when examining which variables neural data could predict, we found that age and SSRT, but not speed or variability of response execution, were predicted by neural activity during successful response inhibition. This predictive relationship provides novel evidence that developmental differences and individual differences in response inhibition are related specifically to inhibitory processes. More generally, this study demonstrates a new approach to identifying the neurocognitive bases of individual differences.
PMCID: PMC2906202  PMID: 20661296
development; predictive analysis; fMRI; response inhibition; stop-signal
15.  Impaired Implicit Learning in Schizophrenia 
Neuropsychology  2008;22(5):606-617.
Schizophrenia patients consistently show deficits on tasks of explicit learning and memory. In contrast, their performance on implicit processing tasks often appears to be relatively intact, though most studies have focused on implicit learning of motor skills. This study evaluated implicit learning in 59 medicated schizophrenia outpatients and 43 healthy controls using two different cognitive skill tasks. Participants completed a Probabilistic Classification task to assess procedural habit learning and an Artificial Grammar task to assess incidental learning of complex rule-based knowledge, as well as an explicit verbal learning and memory task. In addition to performing worse than controls on the explicit learning task, patients showed worse overall performance on the Probabilistic Classification task, which involves gradual learning through trial-by-trial performance feedback. However, patients and controls showed similar levels of learning on the Artificial Grammar task, suggesting a preserved ability to acquire complex rule-based knowledge in the absence of performance feedback. Discussion focuses on possible explanations for schizophrenia patients’ poor Probabilistic Classification task performance.
PMCID: PMC2548320  PMID: 18763880
schizophrenia; implicit learning; neurocognition; habit learning
16.  Remember and Know Judgments During Recognition in Chronic Schizophrenia 
Schizophrenia research  2007;100(1-3):181-190.
Deficits in learning and memory are among the most robust correlates of schizophrenia. It has been hypothesized that these deficits are in part due to reduced conscious recollection and increased reliance on familiarity assessment as a basis for retrieval. The Remember-Know (R-K) paradigm was administered to 35 patients with chronic schizophrenia and 35 healthy controls. In addition to making “remember” and “know” judgments, the participants were asked to make forced choice recognition judgments with regard to details about the learning episode. Analyses comparing response types showed a significant reduction in “remember” responses and a significant increase in “know” responses in schizophrenia patients relative to controls. Both patients and controls recalled more details of the learning episode for “remember” compared to “know” responses, although, in particular for “remember” responses, patients recalled fewer details compared with controls. Notably, patients recognized fewer inter-item but not intra-item stimulus features compared with controls. These findings suggest deficits in organizing and integrating relational information during the learning episode and/or using relational information for retrieval. A Dual-Process Signal Detection interpretation of these findings suggests that recollection in chronic schizophrenia is significantly reduced, while familiarity is not. Additionally, a unidimensional Signal Detection Theory interpretation suggests that chronic schizophrenia patients show a reduction in memory strength, and an altered criterion on the memory strength distribution for detecting new compared with old stimuli but not for detecting stimuli that are remembered versus familiar. Taken together, these findings are consistent with a deficit in recollection and increased reliance on familiarity in making recognition memory judgments in chronic schizophrenia.
PMCID: PMC2517628  PMID: 17964760
schizophrenia; psychosis; chronic; memory; episodic; recognition; recollection; familiarity; context; remember; know

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