Jennifer Barredo

Complimentary Roles of the Hippocampus and Retrosplenial Cortex in Behavioral Context Discrimination

Complex cognitive functions, such as learning and memory, arise from the interaction of multiple brain regions that comprise functional circuits and different components of these circuits make unique contributions to learning. The hippocampus and the retrosplenial cortex (RSC) are anatomically interconnected and both regions are involved in learning and memory. Previous studies indicate that the hippocampus exhibits unique firing patterns for different contexts and that RSC neurons selectively respond to cues that predict reinforcement or the need for a behavioral response, suggesting a hippocampal role in encoding contexts and an RSC role in encoding behaviorally significant cues. To test this, we simultaneously recorded hippocampal and RSC neuronal activity as rats learned to discriminate two behavioral contexts. The rats learned to approach the east arm of a plus maze for reward during the first half of each session and to approach the west arm during the second half. The “go east” and “go west” conditions constitute distinct behavioral contexts, which were cued by the reward location. Neurons in both regions developed highly context‐specific responses as subjects learned to discriminate the contexts, but the response patterns differed in the two brain regions. Consistent with a context processing role, hippocampal neurons developed context‐specific responses to a variety of task stimuli and events. In contrast, RSC neurons only developed context‐specific responses to the reward location, which served as the context identifying cue. These results suggest that the hippocampus and RSC play distinct, but complimentary roles in mediating context appropriate memories and behaviors.

Ventral Fronto-Temporal Pathway Supporting Cognitive Control of Episodic Memory Retrieval

Achieving our goals often requires guiding access to relevant information from memory. Such goal-directed retrieval requires interactions between systems supporting cognitive control, including ventrolateral prefrontal cortex (VLPFC), and those supporting declarative memory, such as the medial temporal lobes (MTL). However, the pathways by which VLPFC interacts with MTL during retrieval are underspecified. Prior neuroanatomical evidence suggests that a polysynaptic ventral fronto-temporal pathway may support VLPFC-MTL interactions. To test this hypothesis, human participants were scanned using fMRI during performance of a source-monitoring task. The strength of source information was varied via repetition during encoding. Single encoding events should produce a weaker memory trace, thus recovering source information about these items should demand greater cognitive control. Results demonstrated that cortical targets along the ventral path--anterior VLPFC, temporal pole, anterior parahippocampus, and hippocampus--exhibited increases in univariate BOLD response correlated with increases in controlled retrieval demand, independent of factors related to response selection. Further, a functional connectivity analysis indicated that these regions functionally couple and are distinguishable from a dorsal pathway related to response selection demands. These data support a ventral retrieval pathway linking PFC and MTL.

The Floor Projection Maze: A novel behavioral apparatus for presenting visual stimuli to rats

There is a long tradition of studying visual learning in rats by presenting stimuli vertically on cards or monitors. The procedures are often labor intensive and the rate of acquisition can be prohibitively low. Available evidence suggests that rats process visual information presented in the lower visual hemifield more effectively than information presented in the upper visual hemifield. We capitalized on these findings by developing a novel apparatus, the Floor Projection Maze, for presenting visual information directly to the floor of an exploratory maze. Two-dimensional (2D) visual stimuli were presented on the floor by back-projecting an image from a standard digital projector to the semi-transparent underside of the floor of an open maze. Long-Evans rats rapidly acquired easy 2D visual discriminations (Experiment 1). Rats were also able to learn a more difficult shape discrimination in dramatically fewer trials than previously reported for the same discrimination when presented vertically (Experiment 2). The two choice discrimination task was adapted to determine contrast sensitivity thresholds in a naïve group of rats (Experiment 3). Contrast sensitivity thresholds were uniform across three subjects, demonstrating that the Floor Projection Maze can be used for visual psychophysics in rats. Our findings demonstrate that rats can rapidly acquire visual tasks when stimuli are presented horizontally on the floor, suggesting that this novel behavioral apparatus will provide a powerful behavioral paradigm in the future.

Network Mechanisms of Clinical Response to Transcranial Magnetic Stimulation in Posttraumatic Stress Disorder and Major Depressive Disorder

BACKGROUND Repetitive transcranial magnetic stimulation (TMS) therapy can modulate pathological neural network functional connectivity in major depressive disorder (MDD). Posttraumatic stress disorder is often comorbid with MDD, and symptoms of both disorders can be alleviated with TMS therapy. This is the first study to evaluate TMS-associated changes in connectivity in patients with comorbid posttraumatic stress disorder and MDD. METHODS Resting-state functional connectivity magnetic resonance imaging was acquired before and after TMS therapy in 33 adult outpatients in a prospective open trial. TMS at 5 Hz was delivered, in up to 40 daily sessions, to the left dorsolateral prefrontal cortex. Analyses used a priori seeds relevant to TMS, posttraumatic stress disorder, or MDD (subgenual anterior cingulate cortex [sgACC], left dorsolateral prefrontal cortex, hippocampus, and basolateral amygdala) to identify imaging predictors of response and to evaluate clinically relevant changes in connectivity after TMS, followed by leave-one-out cross-validation. Imaging results were explored using data-driven multivoxel pattern activation. RESULTS More negative pretreatment connectivity between the sgACC and the default mode network predicted clinical improvement, as did more positive amygdala-to-ventromedial prefrontal cortex connectivity. After TMS, symptom reduction was associated with reduced connectivity between the sgACC and the default mode network, left dorsolateral prefrontal cortex, and insula, and reduced connectivity between the hippocampus and the salience network. Multivoxel pattern activation confirmed seed-based predictors and correlates of treatment outcomes. CONCLUSIONS These results highlight the central role of the sgACC, default mode network, and salience network as predictors of TMS response and suggest their involvement in mechanisms of action. Furthermore, this work indicates that there may be network-based biomarkers of clinical response relevant to these commonly comorbid disorders.

Organization of cortico-cortical pathways supporting memory retrieval across subregions of the left ventrolateral prefrontal cortex

Functional magnetic resonance imaging (fMRI) evidence indicates that different subregions of ventrolateral prefrontal cortex (VLPFC) participate in distinct cortical networks. These networks have been shown to support separable cognitive functions: anterior VLPFC [inferior frontal gyrus (IFG) pars orbitalis] functionally correlates with a ventral fronto-temporal network associated with top-down influences on memory retrieval, while mid-VLPFC (IFG pars triangularis) functionally correlates with a dorsal fronto-parietal network associated with postretrieval control processes. However, it is not known to what extent subregional differences in network affiliation and function are driven by differences in the organization of underlying white matter pathways. We used high-angular-resolution diffusion spectrum imaging and functional connectivity analysis in unanesthetized humans to address whether the organization of white matter connectivity differs between subregions of VLPFC. Our results demonstrate a ventral-dorsal division within IFG. Ventral IFG as a whole connects broadly to lateral temporal cortex. Although several different individual white matter tracts form connections between ventral IFG and lateral temporal cortex, functional connectivity analysis of fMRI data indicates that these are part of the same ventral functional network. By contrast, across subdivisions, dorsal IFG was connected with the midfrontal gyrus and correlated as a separate dorsal functional network. These qualitative differences in white matter organization within larger macroanatomical subregions of VLPFC support prior functional distinctions among these regions observed in task-based and functional connectivity fMRI studies. These results are consistent with the proposal that anatomical connectivity is a crucial determinant of systems-level functional organization of frontal cortex and the brain in general.

Neuroimaging Mechanisms of Therapeutic Transcranial Magnetic Stimulation for Major Depressive Disorder

Research into therapeutic transcranial magnetic stimulation (TMS) for major depression has dramatically increased in the last decade. Understanding the mechanism of action of TMS is crucial to improve efficacy and develop the next generation of therapeutic stimulation. Early imaging research provided initial data supportive of widely held assumptions about hypothesized inhibitory or excitatory consequences of stimulation. Early work also indicated that while TMS modulated brain activity under the stimulation site, effects at deeper regions, in particular, the subgenual anterior cingulate cortex, were associated with clinical improvement. Concordant with earlier findings, functional connectivity studies also demonstrated that clinical improvements were related to changes distal, rather than proximal, to the site of stimulation. Moreover, recent work suggests that TMS modulates and potentially normalizes functional relationships between neural networks. An important observation that emerged from this review is that similar patterns of connectivity changes are observed across studies regardless of TMS parameters. Though promising, we stress that these imaging findings must be evaluated cautiously given the widespread reliance on modest sample sizes and little implementation of statistical validation. Additional limitations included use of imaging before and after a course of TMS, which provided little insight into changes that might occur during the weeks of stimulation. Furthermore, as studies to date have focused on depression, it is unclear whether our observations were related to mechanisms of action of TMS for depression or represented broader patterns of functional brain changes associated with clinical improvement.

Appropriateness of advanced upper limb prosthesis prescription for a patient with cognitive impairment: a case report

Abstract Purpose: To describe a participant with scapulo-thoracic amputation and cognitive impairment trained to use the DEKA Arm and discuss factors relevant to the determination that he was not an appropriate candidate for independent home use of the device. Method: The participant underwent 40 h of in-laboratory training with the DEKA Arm Advanced Upper Limb Prosthesis. Pre-training neuropsychological measures of cognition were collected. Qualitative and quantitative data related to functional performance, quality of life and pain were collected after 10 h of training, and at the conclusion of training. Using a constant comparative approach, data were binned into major themes; elements within each theme were identified. Results: Six themes were relevant to the determination that the participant was inappropriate for home use of the DEKA Arm: physical and mental health; learning, memory and cognition; adult role function; functional performance; user safety and judgement and capacity for independent device use. Issues contraindicating unsupervised device use included: uncontrolled health symptoms, poor knowledge application, safety concerns, absenteeism and performance degradation under stress. Conclusion: The findings have implications for training with and prescription of the DEKA Arm and other complex upper limb prostheses. Further research is needed to develop a model to guide prescription of technologically complex upper limb prostheses. Implications for Rehabilitation Advanced upper limb prostheses, like the DEKA Arm, promise greater functionality, but also may be cognitively demanding, raising questions of when, and if, prescription is appropriate for patients with cognitive impairment. At this time, no formal criteria exist to guide prescription of advanced upper limb prostheses. Each clinical team applies their own informal standards in decision-making. In this case report, we described six factors that were considered in determining whether or not a research participant, with scapulo-thoracic amputation and cognitive impairment was appropriate for home use of a complex upper limb prosthesis. The findings have implications for training with and prescription of the DEKA Arm, and highlights the need for further research to develop prescription guidelines for advanced assistive devices.

Neuropsychological assessment without upper limb involvement: a systematic review of oral versions of the Trail Making Test and Symbol-Digit Modalities Test

ABSTRACT The Trail Making Test (TMT) and written version of the Symbol Digit Modalities Test (SDMT) assess attention, processing speed, and executive functions but their utility is limited in populations with upper limb dysfunction. Oral versions of the TMT and SDMT exist, but a systematic review of their psychometric properties and clinical utility has not been conducted, which was the goal of this study. Searches were conducted in PubMed and PsycINFO, test manuals, and the reference lists of included articles. Four measures were identified: the SDMT-oral, oral TMT-A, oral TMT-B, and the Mental Alternation Test (MAT). Two investigators independently reviewed abstracts to identify peer-reviewed articles that reported on these measures in adult populations. From each article, one investigator extracted information on reliability, validity, responsiveness, minimum detectable change, normative data, and demographic influences. A second investigator verified the accuracy of the data in a random selection of 10% of papers. The quality of the evidence for each psychometric property was rated on a 4-point scale (unknown, poor, adequate, excellent). Results showed excellent evidence for the SDMT-oral, adequate evidence for the oral TMT-B and MAT, and adequate to poor evidence for the oral TMT-A. These findings inform the clinical assessment of attention, processing speed, and executive functions in individuals with upper limb disability.

Cognitive predictors of skilled performance with an advanced upper limb multifunction prosthesis: a preliminary analysis

Abstract Purpose The objectives were to 1) identify major cognitive domains involved in learning to use the DEKA Arm; 2) specify cognitive domain-specific skills associated with basic versus advanced users; and 3) examine whether baseline memory and executive function predicted learning. Method Sample included 35 persons with upper limb amputation. Subjects were administered a brief neuropsychological test battery prior to start of DEKA Arm training, as well as physical performance measures at the onset of, and following training. Multiple regression models controlling for age and including neuropsychological tests were developed to predict physical performance scores. Prosthetic performance scores were divided into quartiles and independent samples t-tests compared neuropsychological test scores of advanced scorers and basic scorers. Baseline neuropsychological test scores were used to predict change in scores on physical performance measures across time. Results Cognitive domains of attention and processing speed were statistically significantly related to proficiency of DEKA Arm use and predicted level of proficiency. Conclusions Results support use of neuropsychological tests to predict learning and use of a multifunctional prosthesis. Assessment of cognitive status at the outset of training may help set expectations for the duration and outcomes of treatment. Implications for Rehabilitation Cognitive domains of attention and processing speed were significantly related to level of proficiencyof an advanced multifunctional prosthesis (the DEKA Arm) after training. Results provide initial support for the use of neuropsychological tests to predict advanced learningand use of a multifunctional prosthesis in upper-limb amputees. Results suggest that assessment of patients’ cognitive status at the outset of upper limb prosthetictraining may, in the future, help patients, their families and therapists set expectations for theduration and intensity of training and may help set reasonable proficiency goals.