Meghan M. Searl

An fMRI Study of the Role of the Medial Temporal Lobe in Implicit and Explicit Sequence Learning

fMRI was used to investigate the neural substrates supporting implicit and explicit sequence learning, focusing especially upon the role of the medial temporal lobe. Participants performed a serial reaction time task (SRTT). For implicit learning, they were naive about a repeating pattern, whereas for explicit learning, participants memorized another repeating sequence. fMRI analyses comparing repeating versus random sequence blocks demonstrated activation of frontal, parietal, cingulate, and striatal regions implicated in previous SRTT studies. Importantly, mediotemporal lobe regions were active in both explicit and implicit SRTT learning. Moreover, the results provide evidence of a role for the hippocampus and related cortices in the formation of higher order associations under both implicit and explicit learning conditions, regardless of conscious awareness of sequence knowledge.

Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance

BACKGROUND Working memory (WM) deficits in schizophrenia have been associated with dorsolateral prefrontal cortex (DLPFC) dysfunction in neuroimaging studies. We previously found increased DLPFC activation in schizophrenic versus normal subjects during WM performance (Manoach et al 1999b). We now have investigated whether schizophrenic subjects recruit different brain regions, particularly the basal ganglia and thalamus, components of frontostriatal circuitry thought to mediate WM. METHODS We examined regional brain activation in nine normal and nine schizophrenic subjects during WM performance using functional magnetic resonance imaging. Subjects performed a modified version of the Sternberg Item Recognition Paradigm that included a monetary reward for correct responses. We compared high and low WM load conditions to each other and to a non-WM baseline condition. We examined activation in both individual subjects and averaged group data. RESULTS Relative to normal subjects, schizophrenic subjects exhibited deficient WM performance, at least an equal magnitude of right DLPFC activation, significantly greater left DLPFC activation, and increased spatial heterogeneity of DLPFC activation. Furthermore, only the schizophrenic group activated the basal ganglia and thalamus, even when matched for task performance with the normal group. CONCLUSIONS Aberrant WM performance and brain activation in schizophrenia may reflect dysfunction of frontostriatal circuitry that subserves WM. Future studies will elucidate the contribution of the anatomical components of this circuitry to WM deficits.

Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI

BACKGROUND Neuroimaging studies of schizophrenic subjects performing working memory (WM) tasks have demonstrated a relative hypoactivity of prefrontal cortex compared with normal subjects. METHODS Using functional magnetic resonance imaging (fMRI), we compared dorsolateral prefrontal cortex (DLPFC) activation in 12 schizophrenic and 10 normal subjects during rewarded performance of a WM task. Subjects performed a modified version of the Sternberg Item Recognition Paradigm (SIRP), a continuous performance, choice reaction time (RT) task that requires WM. We compared a high WM load condition with a nonWM choice RT condition and with a low WM load condition. RESULTS Schizophrenic subjects performed the tasks better than chance but worse than normal subjects. They showed greater activation than normal subjects in the left DLPFC but did not differ in the right DLPFC or in the control region. In the schizophrenic group, left DLPFC activation was inversely correlated with task performance, as measured by errors. CONCLUSIONS These findings contrast with previous studies that demonstrated task-related hypofrontality in schizophrenia. Task parameters that may contribute to this difference are discussed. We hypothesize that the performance and activation differences we observed are also manifestations of prefrontal dysfunction in schizophrenia. They reflect inefficient functioning of the neural circuitry involved in WM.

It is time to talk about people: a human-centered healthcare system

Examining vulnerabilities within our current healthcare system we propose borrowing two tools from the fields of engineering and design: a) Reasons system approach [1] and b) User-centered design [2, 3]. Both approaches are human-centered in that they consider common patterns of human behavior when analyzing systems to identify problems and generate solutions. This paper examines these two human-centered approaches in the context of healthcare. We argue that maintaining a human-centered orientation in clinical care, research, training, and governance is critical to the evolution of an effective and sustainable healthcare system.

Sequence? What Sequence?: the human medial temporal lobe and sequence learning

Medial temporal lobe (MTL) dysfunction is well known to impair performance on conscious ‘explicit’ memory tasks, as when people recognize or recall familiar places, people, and events. In contrast, some unconscious ‘implicit’ types of learning and memory have been thought to be independent of the MTL, depending instead on neocortical and various subcortical structures. An implicit learning and memory task can be any perceptual, cognitive, or motor behavior, such as reading or typing, performed without one necessarily being aware of or consciously trying to use memory representations to influence performance with items that had been previously experienced. Implicit learning and memory effects are evidenced as differences (typically improvements) in performance for learned relative to new information. Convergent findings, especially from studies of human amnesia, have led to explicit–implicit (also declarative–procedural) accounts of learning and memory. By this view, MTL involvement hinges on whether a task requires conscious awareness or intention to learn or remember. However, recent work in animals has begun to cast doubt on the idea that conscious awareness is the primary determinant of MTL involvement. The findings have instead motivated a ‘relational’ account hypothesizing that the MTL is critically involved in associative processes that bind multiple perceptual, cognitive, and motor aspects of events into a flexible memory trace. In contrast to earlier null findings, and favoring a relational view, some recent human neuroimaging and neuropsychological studies suggest that the MTL is necessary also for implicit learning of complex multievent associations. Our neuroimaging study has provided critical evidence, in particular, that the higher-order associative and temporal structure of the representation being acquired is the primary factor determining recruitment of the human MTL. Furthermore, and contrary to an explicit–implicit account, our findings indicate that the MTL plays a role in learning regardless of conscious awareness. Thus, it may be the nature of the representation being formed that serves as the primary determinant of MTL recruitment, while a secondary and emergent property of the representation is its potential accessibility to consciousness. We acquired fMRI data while individuals performed a serial reaction time task (SRTT), first, without being informed of the presence of an embedded, repeating sequence (implicit experiment), and then a second time, after being informed of and while trying to learn the sequence (explicit experiment). On each trial, one of the four visual locations was cued, and participants pressed a key at the corresponding location. Both experiments included trials of a repeating sequence and of random, novel sequences. Critically, response cues were shown in second-order conditional sequences that entail learning of higher-order associations (at least three consecutive locations within the sequence), not merely simple stimulus–stimulus association pairs, within the repeating sequence. Faster response times (RTs) for repeating relative to random sequences demonstrated higher-order sequence learning. We assessed awareness of the repeating sequence by following both experiments with several tests that probed conscious sequence knowledge. Brain activation that is related to learning a higher-order sequence was assessed by comparing data during repeating vs random sequence conditions. Our findings provided clear evidence that the hippocampus, adjacent subiculum, and entorhinal and parahippocampal cortices are critical for both implicit and explicit learning of higher-order associations, regardless of sequence awareness. During both implicit and explicit learning, we obtained strong activation in the MTL, as well as in striatal structures implicated in prior neuroimaging studies of implicit learning and dorsolateral prefrontal cortices implicated in studies of explicit learning. Importantly, the MTL activation was not related to awareness, as conscious sequence knowledge was minimal or absent following implicit learning, yet highly accurate following explicit learning. Moreover, we examined fMRI data from the implicit experiment separately for aware vs unaware subgroups (those showing some vs no significant conscious sequence memory), and found that even participants who were unaware of a repeating sequence had significant MTL activation. The fMRI and behavioral results, together, also indicated that learning-related activity in the MTL is related to the acquisition of higher-order associations. Further, we found that MTL activation is strongest during early learning, but diminishes later when fewer higher-order associations remain to be encoded. Overall, our findings indicate that it is the associative Correspondence: HE Schendan, Center for Memory and Brain, Department of Psychology, Boston University, 2 Cummington Street, Boston, USA. E-mail: haline.schendan@tufts.edu Molecular Psychiatry (2003) 8, 896–897 & 2003 Nature Publishing Group All rights reserved 1359-4184/03

Improving Outcomes in Cancer Patients on Oral Anti-Cancer Medications Using a Novel Mobile Phone-Based Intervention: Study Design of a Randomized Controlled Trial

25.00

The dysexecutive syndromes.

Background The widespread and increasing use of oral anti-cancer medications has been ushered in by a rapidly increasing understanding of cancer pathophysiology. Furthermore, their popular ease of administration and potential cost savings has highlighted their central position in the health care system as a whole. These facts have heightened appreciation of the unique challenges associated with the use of oral anti-cancer medications; especially in the long-term use of these medications and the associated side effects that may impede optimal adherence to their use. Therefore, we developed ChemOtheRapy Assistant, CORA, a personalized mobile phone–based self-management application to help cancer patients on oral anti-cancer medications. Objective Our objective is to evaluate the effect of CORA on adherence to oral anti-cancer medications and other clinically relevant outcomes in the management of patients with renal and prostate cancer. Methods The study will be implemented as a 2-parallel group randomized controlled trial in 104 patients with renal or prostate cancer on oral anti-cancer medications over a 3-month study period. The intervention group will use CORA in addition to usual care for self-management while the control group will continue care as usual. Medication adherence will be measured objectively by a Medication Event Monitoring System device and is defined as the percentage of prescribed doses taken. We will also assess the effect of the intervention on cancer-related symptoms measured by the MD Anderson Symptom Inventory and unplanned hospital utilizations. Other outcomes that will be measured at study start, midpoint, and endpoint are health-related quality of life, cancer-related fatigue, and anxiety. Group differences in medication adherence will be examined by t tests or by non-parametric Mann-Whitney tests if the data are not normally distributed. Logistic regression will be used to identify potential predictors of adherence. Results We expect to have results for this study before the end of 2016. Conclusions This novel mobile phone–enabled, multimodal self-management and educational intervention could lead to improvements in clinical outcomes and serve as a foundation for future mHealth research in improving outcomes for patients on oral anti-cancer medications.

Pain Management in Cancer Patients Using a Mobile App: Study Design of a Randomized Controlled Trial

Publisher Summary This chapter focuses on the dysexecutive syndromes, underlying processing deficits, pathophysiology, clinical assessment, and treatment strategies. Dysexecutive syndromes can develop for numerous reasons. The common factor underlying all dysexecutive syndromes are damage to or disruption of frontal networks (frontal cortex and its connections). Neurodegenerative diseases, CNS infections, traumatic brain injury, neurodevelopmental conditions such as attention deficit/hyperactivity disorder (ADHD) that emerge in childhood are few factors that give rise to dysexecutive syndromes. Clinical assessment of executive functions is also described in the chapter. There are pharmacological and behavioral strategies to help individuals with dysexecutive functioning. Executive functions are among the most valued components of being human. When executive functions fail, the cost to individuals and those who care for them can be extraordinary. There seems to be an increase in growth of clinical assessment tools, diagnostic procedures, and environmental and pharmacological strategies to manage executive dysfunction.

You don't say: dynamic aphasia, another variant of primary progressive aphasia?

Background Despite the availability of effective medications and clinical guidelines for pain management, pain control is suboptimal in a sizeable proportion of patients with cancer pain. The National Comprehensive Cancer Network guidelines recommend a comprehensive and multimodal approach for management of cancer pain. We developed a mobile phone application, ePAL, based on clinical guidelines to empower patients for cancer pain management by prompting regular pain assessments and coaching for self-management. Objective The objective of this study is to evaluate the effect of a multidimensional mobile phone-based pain management application, ePAL, on controlling cancer pain and improving quality of life in patients with cancer pain being treated at an academic palliative care clinic. Methods The study will be implemented as a 2-arm randomized controlled trial with 110 adult patients with CP who own a mobile phone over a follow-up period of two months. Participants will be randomized to either the intervention group receiving ePAL and usual care or to a control group receiving only usual care. The brief pain inventory will be used to assess our primary outcome which is pain intensity. We will also evaluate the effect of the intervention on secondary outcomes which include the effect of the intervention on hospital utilization for pain crisis, quality of life, adherence to analgesic medications, barriers to pain control, anxiety and patient engagement. Instruments that will be used in evaluating secondary outcomes include the Brief Pain Inventory, Morisky Medication Adherence Scale, Barriers Questionnaire-II, Functional Assessment of Cancer Therapy–General, Edmonton Symptom Assessment System, Generalized Anxiety Disorder 7-item scale, and the Functional Assessment of Chronic Illness Therapy-Fatigue. The intention-to-treat approach will be used to evaluate outcomes. Our primary outcome, pain intensity, measured longitudinally over eight weeks, will be assessed by mixed model repeated analysis. Effect sizes will be calculated as mean group differences with standard deviations. Results The study is still in progress. We hope to have results by the end of 2015. Conclusions The multidimensional approach to pain management implemented on a mobile phone application could lead to significant improvements in patient outcomes. Trial Registration ClinicalTrials.gov NCT02069743; https://clinicaltrials.gov/ct2/show/NCT02069743 (Archived by WebCite at http://www.webcitation.org/6Qb65XGGA).

IQ-BASED NORMS FOR HIGHLY INTELLIGENT ADULTS

Primary progressive aphasia (PPA) is a language predominant neurodegenerative disorder that has three recognized variants: nonfluent/agrammatic, semantic, and logopenic. This report describes a 60-year-old man who presented with a progressive decline in verbal output that does not fit the currently accepted PPA subtypes. The patient exhibited a paucity of verbal output and impaired phonemic fluency with minimal associated language, cognitive, or behavioral deficits. Focal cortical thinning/hypometabolism of the left superior frontal region and a cerebrospinal fluid profile not consistent with Alzheimers disease pathology were identified. This case of isolated progressive dynamic aphasia extends the current boundaries of PPA diagnostic variants.