Daniel Drane - US grants

DESCRIPTION (provided by applicant): We believe that a thorough examination of category-specific recognition and naming abilities in temporal lobe epilepsy (TLE) patients who have been well-studied before and after respective surgery can resolve inconsistencies that exist regarding the neural substrates and organization of category-specific information. Systematic exploration of category-specific functions both pre- and postoperatively with specially designed neurocognitive tests, quantitative volumetric MRI, and intraoperative language assessment will allow us to determine the relationship between TL sites, potential mediating variables (e.g., atypical naming sites, epilepsy duration), and the naming/recognition functions disturbed in patients exhibiting category specific deficits. We have employed Damasio's "mediational/convergence zone" model of semantic memory as a heuristic framework to generate testable hypotheses for exploring these deficits. Based on this model, one would expect category-specific deficits to routinely occur following TL resections, and preliminary data obtained in our lab support this prediction. These deficits are frequently missed by commonly employed naming measures, despite evidence that they compromise neurocognitive and functional status. Elucidating these constructs will lead to more precise models of semantic memory, and may reveal that some patients undergoing TL resection are at risk for experiencing significant category-specific deficits. Such findings could lead to changes in surgical technique and the selection of surgical candidates, and contribute to improvements in neurocognitive outcome. The PI, who serves as a neuropsychologist/Assistant Professor in the UW Department of Neurology, can draw upon the resources and patient population of a well established epilepsy program. This proposal, if funded, would enable him to develop the necessary skills to mesh his neuropsychological training with advances in neuroimaging and related technologies in an effort to more precisely study brain-behavior relationships, while establishing him as an independent clinician scientist.

DESCRIPTION (provided by applicant): Semantic Deficits in Temporal Lobe Epilepsy Surgical Patients may represent a Structural Connectivity Problem: Exploration with Diffusion Imaging Abstract Semantic memory reflects one's knowledge of factual information about the world and one's experiences, while semantic processing more broadly relates to the act of accessing this stored knowledge. Although a great deal has been learned about semantic processing from both lesion studies and neuroimaging paradigms, great uncertainty remains regarding the neural mechanisms involved in these processes and the representation of conceptual information in the brain. Our research with temporal lobe epilepsy (TLE) surgical patients demonstrates that language dominant anterior temporal lobe (ATL) dysfunction is associated with category-related naming problems while nondominant ATL dysfunction is associated with category-related deficits in visual recognition and familiarity judgments. Category-related deficits are frequently present preoperatively in TLE patients, and worsen dramatically in many patients following surgery. Our data suggests nearly all adult onset TLE patients exhibit such declines while many of the early onset patients do not (likely reflecting reorganization of function in the latter group). Preliminary data indicate that some patients experience significant compromise of vocational and/or social functioning due to these limitations; with many experiencing concomitant emotional/psychiatric distress. Nevertheless, these deficits have gone virtually unrecognized by the epilepsy surgical community. Our data indicate that these naming, recognition, and familiarity deficits reflect disconnection syndromes, as core components of functioning (e.g., language, visual processing, semantic knowledge) appear intact despite task failures occurring when our measures require interaction between them. We also present several different examples demonstrating that altering task demands can facilitate or hinder performance. For example, patients with naming deficits typically select the correct object name when provided with a multiple choice recognition format, yet are again unable to spontaneously name the same visual image presented only minutes later. Research demonstrates that neural regions in the ATL and the white matter (WM) pathways that connect them to other key brain areas underlie our ability to recognize and name certain object categories. As diffusion tensor imaging (DTI) and subcortical electrostimulation mapping of the WM suggest that damage to these tracts is sufficient to cause recognition and naming deficits, we believe that the disruption of these WM tracts (due to physiological changes related to seizures preoperatively or surgical transection) contributes to these deficits in TLE patients. Therefore, we propose using DTI to determine the relationship between category-related naming and visual recognition performance and WM pathways that lie at the core of the neural circuits that subsume these processes. If we can identify the critical WM pathways, in the future it can be ensured that these are spared by the neurosurgeon by altering surgical approach or using alternative techniques (e.g., Gamma Knife, responsive stimulation mapping), thus preventing devastating deficits in naming, recognition of faces/objects, and complex semantic learning. We will demonstrate the key pathways by establishing which tracts that traverse the TL regions of each cerebral hemisphere are strongly correlated with baseline performance, and by examining which are compromised when category-related deficits are observed. Our study represents an important step towards understanding these circuits, and will allow us to create preoperative diffusion imaging maps to guide surgical intervention in conjunction with stealth technology or intraoperative MRI for patients undergoing surgery involving the anterior TLs. This is consistent with the NIH Curing Epilepsy goal of improving the clinical outcome of epilepsy patients, and has broader implications for patients undergoing other neurosurgical interventions and diseases of the TLs. In subsequent studies we hope to combine diffusion imaging techniques with functional connectivity paradigms in order to study the broader neural circuits involved in supporting these cognitive functions. The current K02 award mechanism will provide Dr. Drane with the necessary training to effectively analyze the data obtained with these neuroimaging tools, while further determining the contribution of WM to these cognitive skills. We feel it is imperative for a clinical researcher to be skilled in these advanced diffusion imaging techniques (given their absence in most clinical settings) in order to insure that this procedure gets validated at the level of the individual, and translated into regular clinical use. We also hope that this project will allow us to turn our research protocol into a clinical measure of category-related naming and recognition performance that can be disseminated throughout the epilepsy surgical community, as no measures of this type are currently available. Finally, our research also has intrinsic value to neuroscience, as we can make great strides in mapping the neural circuitry of the semantic memory system in a manner that is not possible in healthy controls or patients with other neurological diseases.

DESCRIPTION (provided by applicant): Epilepsy surgery involving the anteromedial temporal lobe (ATL) often results in verbal memory and naming decline following language dominant resection and in visual memory decline after nondominant resection. We have shown open ATL resections also frequently result in recognition or naming declines for several object types (e.g., famous persons) and related functions (e.g., proper noun fluency). These deficits, not previously recognized as clinical risks, compromise functional status and compound the burden of memory decline. We propose these deficits reflect collateral damage incurred when surgically accessing the mesial TL. Our ongoing NINDS K02 award uses DTI probabilistic tractography to determine if decline results from damage to specific white matter (WM) paths. This K02 is laying the groundwork for developing surgical options to improve cognitive outcome by sparing key paths underlying these functions. Preliminary data show several WM paths are related to baseline performance on these measures, and resection of specific tracts leads to predicted decline. Our R01 proposal uses a novel, minimally invasive, MRI-guided laser ablation technique, selective laser amygdalohippocampotomy (SLAH), to directly test our collateral damage hypothesis. SLAH ablates at least 50% of hippocampus and amygdala, but does not directly damage WM due to its minimally invasive nature. We hypothesize damage restricted to these structures will not lead to naming and recognition deficits, consistent with our preliminary data. This allows us to assess the popular view that mesial TL structures are essential to these processes, which has arisen from indirect paradigms (fMRI/stimulation mapping). Our clinical data also indicate most SLAH patients do not experience episodic memory decline, again contrary to prevailing views of hippocampal function. We propose better memory outcomes after SLAH results from: (a) sparing surrounding mesial TL structures; and (b) less direct and secondary degenerative damage to WM paths away from the resection zone. We predict patients undergoing SLAH will not experience naming and recognition deficits, and will exhibit a significantly better outcome than open resection patients. We predict WM tracts included in open resections will contribute to performance declines on these tasks, but not hippocampal and amygdalar resection volumes. Secondly, we evaluate the contribution of the hippocampus and amygdala to episodic memory functions, predicting greater memory deficits following open resection compared to SLAH. Lastly, we will explore secondary changes in non-resected WM tracts using MRI diffusion parameters, predicting greater improvement in these parameters after SLAH versus open resection. We hypothesize diffusivity improvements in these non-resected tracts and contralateral hippocampus will correlate with improved memory scores (greatest for the SLAH cohort). In sum, this research allows us to: (a) dissociate the contribution of amygdala and hippocampus from that of the overlying cortex and TL WM paths to key cognitive functions, and (b) determine if SLAH preserves cognitive functions frequently affected by open resections.

Project Summary: We have conducted the largest prospective comparative study of laser amygdalohippocampotomy (SLAH), a minimally invasive procedure ablating the amygdalo-hippocampal complex (AHC) versus selective and standard open resection (OR) epilepsy surgery (N=425+). We demonstrated that SLAH is superior to OR in 1-year cognitive outcomes in adults (including episodic verbal memory & perceptual (semantic) recognition or name retrieval of objects/faces), while achieving comparable seizure control. We will extend our analysis longitudinally in an unprecedented manner (5-10 year outcome) leveraging this unique cohort of well-studied patients including neuropsychological (NP), structural and functional neuroimaging and seizure outcomes. We have also amassed a large sample of cases involving stereotactic laser ablation [SLA] of non-AHC structures. The heterogeneity of these SLA cases and the focal nature of the laser ablation surgical zones create an amazing opportunity for lesion-behavioral analyses. We will expand our neuroimaging analyses to include rigorous voxel lesion symptom mapping (VLSM) and novel methods of connectivity modeling with diffusion tensor imaging and resting state fMRI. We will focus on the neural circuitry responsible for declarative memory and language, while determining the optimal surgical zones to produce the best long-term cognitive and seizure outcomes. VLSM allows us to determine which temporal lobe regions are critical for specific cognitive functions, while connectivity analyses will reveal the interconnectedness of these regions in the individual patient (allowing us to determine the relative risk of decline at the patient level). Our preliminary findings indicate that: 1) SLAH patients exhibit unexpected improvement in multiple cognitive functions, which is unparalleled in their OR counterparts, and 2) SLA procedures sparing the AHC and broader medial TL regions frequently lead to severe decline in verbal memory/naming, particularly in cases of focal ablations of the language dominant temporal pole or fusiform gyrus. This suggests that verbal declarative memory depends upon a broad network extending beyond the AHC, which is a paradigm shift for surgical planning (i.e., regions thought to be expendable during surgical approach are actually critical to function). This knowledge is fundamentally important from mechanistic and clinical translational points of view, and our data and planned analyses provide a unique and feasible way to draw robust conclusions on these long-standing knowledge gaps. Our data raise pivotal questions about existing declarative memory models and the mechanism of recovery underlying the superior cognitive outcomes in many SLAH/SLA cases (e.g., functional sparing vs. reorganization), which we will address in this renewal by following our patients over time. Finally, while more epilepsy centers are employing SLA due to its improved cognitive outcomes, ultimate clinical adoption rests on seizure control, making it critical to determine SLAH efficacy over a longer time span.

Project Summary This proposal aims to develop a National Neuropsychology Network (NNN), starting with four clinical research sites in California, Florida, Georgia, and Wisconsin. The NNN aims to gather clinical diagnostic information following a shared protocol, collect item-level data on representative neuropsychological (NP) instruments, and deposit these data in the NIMH Data Archive (NDA; https://data-archive.nimh.nih.gov/), more specifically in the Research Domains Criteria database (RDoCdb). The infrastructure established in the network focuses on point- of-testing data acquisition, using iPads, leveraging existing technology developed by a leading test vendor (Q- interactive, from Pearson), and developing additional software to collect specific additional measures that are widely used in clinical neuropsychology laboratories and clinics but which are not available elsewhere. The NNN will collect data on more than 10,000 cases over 4 years, representing a broad range of neuropsychiatric disorders, reflecting populations seen nationwide, and then deposit all data in RDoCdb. Data analyses will specify the latent constructs underlying each test, the factors represented by larger batteries, and create proposals for new individual tests and batteries. Novel tests (short forms and adaptive tests) will be suggested based on item-response theory modeling of each test, with desired precision of measurement for evidence- based clinical decision-making. Novel battery proposals will be informed by examining the positive and negative predictive power of each test to contribute to key differential diagnostic questions that arise in NP assessment. Both battery and individual test proposals will focus on efficiency, and are expected to yield at least a doubling of efficiency. The NNN aims to serve as a nucleus and template for additional network nodes, that will in its next generation offer a national platform for co-norming novel tests, expanding to other languages, and ultimately designing new procedures that are validated with respect to both brain function and real world adaptive capacities.

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