Deep brain stimulation of the anterior thalamus attenuates PTZ kindling with concomitant reduction of adenosine kinase expression in rats.

BACKGROUND: Deep brain stimulation (DBS) of the anterior nucleus of the thalamus (ANT) is an emerging therapy to provide seizure control in patients with refractory epilepsy, although its therapeutic mechanisms remain elusive. OBJECTIVE: We tested the hypothesis that ANT-DBS might interfere with the kindling process using three experimental groups: PTZ, DBS-ON and DBS-OFF. METHODS: 79 male rats were used in two experiments and exposed to chemical kindling with pentylenetetrazole (PTZ, 30 mg/kg i.p.), delivered three times a week for a total of 18 kindling days (KD). These animals were divided into two sets of three groups: PTZ (n = 26), DBS-ON (n = 28) and DBS-OFF (n = 25). ANT-DBS (130 Hz, 90 µs, and 200 µA) was paired with PTZ injections, while DBS-OFF group, although implanted remained unstimulated. After KD 18, the first set of PTZ-treated animals and an additional group of 11 naïve rats were euthanized for brain extraction to study adenosine kinase (ADK) expression. To observe possible long-lasting effects of ANT stimulation, the second set of animals underwent a 1-week treatment and stimulation-free period after KD 18 before a final PTZ challenge. RESULTS: ANT-DBS markedly attenuated kindling progression in the DBS-ON group, which developed seizure scores of 2.4 on KD 13, whereas equivalent seizure scores were reached in the DBS-OFF and PTZ groups as early as KD5 and KD6, respectively. The incidence of animals with generalized seizures following 3 consecutive PTZ injections was 94%, 74% and 21% in PTZ, DBS-OFF and DBS-ON groups, respectively. Seizure scores triggered by a PTZ challenge one week after cessation of stimulation revealed lasting suppression of seizure scores in the DBS-ON group (2.7 ± 0.2) compared to scores of 4.5 ± 0.1 for the PTZ group and 4.3 ± 0.1 for the DBS-OFF group (P = 0.0001). While ANT-DBS protected hippocampal cells, the expression of ADK was decreased in the DBS-ON group compared to both PTZ (P < 0.01) and naïve animals (P < 0.01). CONCLUSIONS: Our study demonstrates that ANT-DBS interferes with the kindling process and reduced seizure activity was maintained after a stimulation free period of one week. Our findings suggest that ANT-DBS might have additional therapeutic benefits to attenuate seizure progression in epilepsy.

Frameless Robotic-Assisted Deep Brain Stimulation With the Mazor Renaissance System.

BACKGROUND: Robotic-assisted stereotactic systems for deep brain stimulation (DBS) have recently gained popularity because of their abilities to automate arduous human error-prone steps for lead implantation. Recent DBS literature focuses on frame-based robotic platforms, but little has been reported on frameless robotic approaches, specifically the Food and Drug Administration-approved Mazor Renaissance Guidance System (Mazor Robotics Ltd). OBJECTIVE: To present an initial case series for patients undergoing awake DBS with the Mazor Renaissance Guidance System and evaluate operative variables and stereotactic accuracy. METHODS: Retrospective data collection at a single institution was conducted for an initial 35 consecutive patients. Patient demographics and operative variables, including case times, microelectrode recording passes, and postoperative complications, were obtained by chart review. Implant accuracy was evaluated through measuring radial and vector (x, y) errors using the Mazor software. Pneumocephalus volumes were calculated using immediate postoperative T1-weighted MRI scans. RESULTS: Total operating room (245 ± 5.5 min) and procedural (179 ± 4.7) times were comparable with previous awake DBS literature. The radial error for center tract implants was 1.3 ± 0.1 mm, with smaller error in the first (1.1 ± 0.2) vs second (1.7 ± 0.3) implants of bilateral DBS (P = .048). Vector error analysis demonstrated larger shifts posteriorly for first implants and medially for second implants. Pneumocephalus volumes (12.4 ± 2.2 cm3) were not associated with increased microelectrode recording passes, radial error, or complications. CONCLUSION: Frameless robotic-assisted DBS is a safe and efficient new technology that has been easily adopted into the workflow at our institution.

Is It Possible to Save the Deep Brain Stimulation Hardware when Presenting with Wound Dehiscence or Hardware Infection?

INTRODUCTION: Deep brain stimulation (DBS) hardware complications have been traditionally managed by removal of the entire system. Explantation of the system results in prolonged interruption to the patient's care and potential challenges when considering reimplantation of the cranial leads. The purpose of this study was to understand whether complete explantation can be avoided for patients initially presenting with wound dehiscence and/or infection of hardware. METHODS: We performed a retrospective study that included 30 cases of wound dehiscence or infection involving the DBS system. Patients underwent reoperation without explantation of the DBS system, with partial explanation, or with complete explantation as initial management of the complication. RESULTS: A total of 17/30 cases were managed with hardware-sparing wound revisions. The majority presented with wound dehiscence (94%), with the scalp (n = 9) as the most common location. This was successful in 76.5% of patients (n = 13). Over 11/30 patients were managed with partial explantation. The complication was located at the generator (91%) or at the scalp (9%). Partial explantation was successful in 64% of patients (n = 7). In cases that underwent a lead-sparing approach, 33% of patients ultimately required removal of the intracranial lead, and 2/30 cases of hardware infection were managed initially with total explantation. DISCUSSION/CONCLUSION: Wound dehiscence can be successfully managed without complete removal of the DBS system in most cases. In cases of infection, removing the involved component(s) and sparing the intracranial leads may be considered. Wound revision without removal of the entire DBS system is safe and can improve quality of life by preventing or shortening the withdrawal of DBS treatment.

The contributions of entorhinal cortex and hippocampus to error driven learning.

Computational models proposed that the medial temporal lobe (MTL) contributes importantly to error-driven learning, though little direct in-vivo evidence for this hypothesis exists. To test this, we recorded in the entorhinal cortex (EC) and hippocampus (HPC) as macaques performed an associative learning task using an error-driven learning strategy, defined as better performance after error relative to correct trials. Error-detection signals were more prominent in the EC relative to HPC. Early in learning hippocampal but not EC neurons signaled error-driven learning by increasing their population stimulus-selectivity following error trials. This same pattern was not seen in another task where error-driven learning was not used. After learning, different populations of cells in both the EC and HPC signaled long-term memory of newly learned associations with enhanced stimulus-selective responses. These results suggest prominent but differential contributions of EC and HPC to learning from errors and a particularly important role of the EC in error-detection.

Magnetic Resonance-Guided Laser-Induced Thermal Therapy for the Treatment of Progressive Enhancing Inflammatory Reactions Following Stereotactic Radiosurgery, or PEIRs, for Metastatic Brain Disease.

BACKGROUND: In patients who have previously undergone maximum radiation for metastatic brain tumors, a progressive enhancing inflammatory reaction (PEIR) that represents either tumor recurrence or radiation necrosis, or a combination of both, can occur. Magnetic resonance-guided laser-induced thermal therapy (LITT) offers a minimally invasive treatment option for this problem. OBJECTIVE: To report our single-center experience using LITT to treat PEIRs after radiosurgery for brain metastases. METHODS: Patients with progressive, enhancing reactions at the site of prior radiosurgery for metastatic brain tumors and who had a Karnofsky performance status of ≥70 were eligible for LITT. The primary endpoint was local control. Secondary end points included dexamethasone use and procedure-related complications. RESULTS: Between 2010 and 2017, 59 patients who underwent 74 LITT procedures for 74 PEIRs met inclusion criteria. The mean pre-LITT PEIR size measured 3.4 ± 0.4 cm3. At a median follow-up of 44.6 wk post-LITT, the local control rate was 83.1%. Most patients were weaned off steroids post-LITT. Patients experiencing a post-LITT complication were more likely to remain on steroids indefinitely. The rate of new permanent neurological deficit was 3.4%. CONCLUSION: LITT is an effective treatment for local control of PEIRs after radiosurgery for metastatic brain disease. When possible, we recommend offering LITT once PEIRs are identified and prior to the initiation of high-dose steroids for symptom relief.

Ablation dynamics of subsequent thermal doses delivered to previously heat-damaged tissue during magnetic resonance-guided laser-induced thermal therapy.

OBJECTIVE: Intraoperative dynamics of magnetic resonance-guided laser-induced thermal therapy (MRgLITT) have been previously characterized for ablations of naive tissue. However, most treatment sessions require the delivery of multiple doses, and little is known about the ablation dynamics when additional doses are applied to heat-damaged tissue. This study investigated the differences in ablation dynamics between naive versus damaged tissue. METHODS: The authors examined 168 ablations from 60 patients across various surgical indications. All ablations were performed using the Visualase MRI-guided laser ablation system (Medtronic), which employs a 980-nm diffusing tip diode laser. Cases with multiple topographically overlapping doses with constant power were selected for this study. Single-dose intraoperative thermal damage was used to calculate ablation rate based on the thermal damage estimate (TDE) of the maximum area of ablation achieved (TDEmax) and the total duration of ablation (tmax). We compared ablation rates of naive undamaged tissue and damaged tissue exposed to subsequent thermal doses following an initial ablation. RESULTS: TDEmax was significantly decreased in subsequent ablations compared to the preceding ablation (initial ablation 227.8 ± 17.7 mm2, second ablation 164.1 ± 21.5 mm2, third ablation 124.3 ± 11.2 mm2; p = < 0.001). The ablation rate of subsequent thermal doses delivered to previously damaged tissue was significantly decreased compared to the ablation rate of naive tissue (initial ablation 2.703 mm2/sec; second ablation 1.559 mm2/sec; third ablation 1.237 mm2/sec; fourth ablation 1.076 mm/sec; p = < 0.001). A negative correlation was found between TDEmax and percentage of overlap in a subsequent ablation with previously damaged tissue (r = -0.164; p < 0.02). CONCLUSIONS: Ablation of previously ablated tissue results in a reduced ablation rate and reduced TDEmax. Additionally, each successive thermal dose in a series of sequential ablations results in a decreased ablation rate relative to that of the preceding ablation. In the absence of a change in power, operators should anticipate a possible reduction in TDE when ablating partially damaged tissue for a similar amount of time compared to the preceding ablation.

Volumetric trends of progressive in-field recurrences after stereotactic radiosurgery of metastatic intracranial tumors.

OBJECTIVE: Local recurrence after stereotactic radiosurgery for brain metastasis is a well-known problem. We analyzed volumetric trends from the time of radiosurgery to time of treatment to understand progression behavior. METHODS: A retrospective review of patients who underwent treatment for post-radiation progressive lesions was performed. Volumetric trends were obtained by plotting individual lesion volumes from the post-radiation nadir volume to volume at treatment and then fitted to exponential decay or linear regressions. RESULTS: Twenty-eight post-radiation recurrences demonstrated exponential growth and thirteen followed a linear pattern. For lesions exhibiting exponential growth, the average nadir volume was 0.26cm3 (SEM=0.06) at an average of 298 days before treatment and mean volume at treatment was 2.39cm3 (SEM=0.33). The average adjusted R2 was 0.94 (SEM=0.013) and doubling factor was 68.60days (SEM=12.55). In the linear growth cohort, the mean nadir volume was 1.43cm3 (SEM=0.25) at an average of 158 days before treatment and average volume at treatment was 6.90cm3 (SEM=1.43). The mean R2 was 0.92 (SEM=0.02) and average growth rate was 0.034cm3/day. Majority of lesions from primary non-small cell lung cancer (81%) and breast cancer (63%) followed exponential growth. CONCLUSIONS: Exponential and linear regressions are accurate representations of post-radiation progression behavior and may be valuable in understanding the growth patterns for recurrences ultimately requiring treatment.

Assessment of Optimal Imaging Protocol Sequences After Laser-Induced Thermal Therapy for Intracranial Tumors.

BACKGROUND: Magnetic resonance-guided laser-induced thermal therapy (MRgLITT) is a novel, minimally invasive method currently being used to treat a wide range of intracranial pathologies. No accepted guidelines exist on what the appropriate magnetic resonance imaging (MRI) sequences are for evaluating short-term postablation changes, especially when patients are not able to receive gadolinium. OBJECTIVE: To evaluate which MRI sequences provide the greatest inter-rater reliability and least amount of variability in assessment of ablation volume after MRgLITT for intracranial neoplasms. METHODS: Twenty patients who received MRgLITT were included. Three raters calculated volumetric measurements on postprocedural axial spoiled gradient recalled (SPGR), fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and gradient echo (GRE) sequences. Measured volumes were analyzed using intraclass correlation to determine which protocol had the most concordance among the 3 raters. RESULTS: Postcontrast SPGR sequences were most concordant in our study, with an intraclass correlation of 0.981. DWI was the next-most concordant imaging sequence with an intraclass correlation of 0.958. The least concordant were GRE (0.895) and FLAIR (0.866) images. SPGR was also the least variable and had the most consistent volume ratings compared to the other sequences. CONCLUSION: This study is the first to evaluate the inter-rater reliability of different MRI sequence protocols in the context of post-MRgLITT volumetric evaluation. SPGR postcontrast images facilitate the greatest interobserver concordance when characterizing post-MRgLITT tumor appearance and volumetrics, with DWI ranked second. Based on our findings, SPGR sequences are likely to yield the highest degree of concordance in post-MRgLITT lesion evaluation. When gadolinium cannot be given, DWI should provide the next most reliable estimation.

Effects of variable power on tissue ablation dynamics during magnetic resonance-guided laser-induced thermal therapy with the Visualase system.

PURPOSE: Magnetic resonance-guided laser-induced thermal therapy (MRgLITT) is a minimally invasive procedure used to treat various intracranial pathologies. This study investigated the effects of variable power on maximal estimated thermal damage during ablation and duration required to reach maximal ablation. MATERIALS/METHODS: All ablations were performed using the Visualase Thermal Therapy System (Medtronic Inc., Minneapolis, Minnesota), which uses a 980 nm diffusing tip diode laser. Cases were stratified into low, medium and high power. Maximal thermal damage estimate (TDEmax) achieved in a single plane and time to reach maximal damage (ttdemax) were measured and compared between groups using a 2×3 Fixed Factor Analysis of Covariance. Ablation area change for cases in which an initial thermal dose was followed by a subsequent dose, with increased power, was also assessed. RESULTS: We used real-time ablation data from 93 patients across various intracranial pathologies. ttdemax (mean ± SEM) decreased linearly as power increased (low: 139.2 ± 10.4 s, medium: 127.5 ± 4.3 s, high: 103.7 ± 5.8 s). In cases where a second thermal dose was delivered at higher power, the TDE expanded an average of 51.4 mm2 beyond the initial TDE generated by the first ablation, with the second ablation approaching TDEmax at a higher rate than the initial ablation. CONCLUSION: Increased power results in a larger TDEmax and an increased ablation rate. In cases where an initial thermal dose does not fully ablate the target lesion, a second ablation at higher power can increase the area of ablation with an increased ablation rate.

Are there right hemisphere contributions to visually-guided movement? Manipulating left hand reaction time advantages in dextrals.

Many studies have argued for distinct but complementary contributions from each hemisphere in the control of movements to visual targets. Investigators have attempted to extend observations from patients with unilateral left- and right-hemisphere damage, to those using neurologically-intact participants, by assuming that each hand has privileged access to the contralateral hemisphere. Previous attempts to illustrate right hemispheric contributions to the control of aiming have focussed on increasing the spatial demands of an aiming task, to attenuate the typical right hand advantages, to try to enhance a left hand reaction time advantage in right-handed participants. These early attempts have not been successful. The present study circumnavigates some of the theoretical and methodological difficulties of some of the earlier experiments, by using three different tasks linked directly to specialized functions of the right hemisphere: bisecting, the gap effect, and visuospatial localization. None of these tasks were effective in reducing the magnitude of left hand reaction time advantages in right handers. Results are discussed in terms of alternatives to right hemispheric functional explanations of the effect, the one-dimensional nature of our target arrays, power and precision given the size of the left hand RT effect, and the utility of examining the proportions of participants who show these effects, rather than exclusive reliance on measures of central tendency and their associated null hypothesis significance tests.

Optimizing computational feature sets for subthalamic nucleus localization in DBS surgery with feature selection.

OBJECTIVE: Microelectrode recording (MER) is used to identify the subthalamic nucleus (STN) during deep brain stimulation (DBS) surgery. Automated STN detection typically involves extracting quantitative features from MERs for classifier training. This study evaluates the ability of feature selection to identify optimal feature combinations for automated STN localization. METHODS: We extracted 13 features from 65 MERs for classifier training. For logistic regression (LR) classification, we compared classifiers identified by feature selection to those containing all possible feature combinations. We used classification error as our metric with hold-one-patient-out cross-validation. We also compared patient-specific vs. independent normalization on classifier performance. RESULTS: Feature selection and patient-specific normalization were superior to non-optimized, patient-independent classifiers. Feature selection, patient-specific normalization, and both produced relative error reductions of 4.95%, 31.36%, and 38.92%, respectively. Three of four feature-selected LR classifiers performed better than 99% of classifiers with all possible feature combinations. Optimal feature combinations were not predictable from individual feature performance. CONCLUSIONS: Feature selection reduces classification error in automated STN localization from MERs. Additional improvement from patient-specific normalization suggests these approaches are necessary for clinically reliable automation of MER interpretation. SIGNIFICANCE: These findings represent an incremental advance in automated functional localization of STN from MER in DBS surgery.

The rationale driving the evolution of deep brain stimulation to constant-current devices.

OBJECTIVE: Deep brain stimulation (DBS) is an effective therapy for the treatment of a number of movement and neuropsychiatric disorders. The effectiveness of DBS is dependent on the density and location of stimulation in a given brain area. Adjustments are made to optimize clinical benefits and minimize side effects. Until recently, clinicians would adjust DBS settings using a voltage mode, where the delivered voltage remained constant. More recently, a constant-current mode has become available where the programmer sets the current and the stimulator automatically adjusts the voltage as impedance changes. METHODS: We held an expert consensus meeting to evaluate the current state of the literature and field on constant-current mode versus voltage mode in clinical brain-related applications. RESULTS/CONCLUSIONS: There has been little reporting of the use of constant-current DBS devices in movement and neuropsychiatric disorders. However, as impedance varies considerably between patients and over time, it makes sense that all new devices will likely use constant current.

Magnetic resonance-guided laser ablation improves local control for postradiosurgery recurrence and/or radiation necrosis.

BACKGROUND: Enhancing lesions that progress after stereotactic radiosurgery are often tumor recurrence or radiation necrosis. Magnetic resonance-guided laser-induced thermal therapy (LITT) is currently being explored for minimally invasive treatment of intracranial neoplasms. OBJECTIVE: To report the largest series to date of local control with LITT for the treatment of recurrent enhancing lesions after stereotactic radiosurgery for brain metastases. METHODS: Patients with recurrent metastatic intracranial tumors or radiation necrosis who had previously undergone radiosurgery and had a Karnofsky performance status of >70 were eligible for LITT. Sixteen patients underwent a total of 17 procedures. The primary end point was local control using magnetic resonance imaging scans at intervals of >4 weeks. Radiographic outcomes were followed up prospectively until death or local recurrence (defined as >25% increase in volume compared with the 24-hour postprocedural scan). RESULTS: Fifteen patients (age, 46-82 years) were available for follow-up. Primary tumor histology was non-small-cell lung cancer (n = 12) and adenocarcinoma (n = 3). On average, the lesion size measured 3.66 cm (range, 0.46-25.45 cm); there were 3.3 ablations per treatment (range, 2-6), with 7.73-cm depth to target (range, 5.5-14.1 cm), ablation dose of 9.85 W (range, 8.2-12.0 W), and total ablation time of 7.43 minutes (range, 2-15 minutes). At a median follow-up of 24 weeks (range, 4-84 weeks), local control was 75.8% (13 of 15 lesions), median progression-free survival was 37 weeks, and overall survival was 57% (8 of 14 patients). Two patients experience recurrence at 6 and 18 weeks after the procedure. Five patients died of extracranial disease progression; 1 patient died of neurological progression elsewhere in the brain. CONCLUSION: Magnetic resonance imaging-guided LITT is a well-tolerated procedure and may be effective in treating tumor recurrence/radiation necrosis.

Volumetric trends associated with MRI-guided laser-induced thermal therapy (LITT) for intracranial tumors.

BACKGROUND: MR-guided Laser Induced Thermal Therapy (LITT) is a procedure for intracranial tumors. Minimal data exists regarding post-procedure lesion volume changes. OBJECTIVES: We aim to analyze changes in lesion volume during the post-LITT period using polygonal tracing with fusion. Additionally, we investigated the role of lesion histopathology on LITT parameters and volume dynamics. METHODS: Sixteen patients with intracranial neoplasms received LITT. Using OsiriX DICOM Viewer, three raters computed lesion volumes at the following: pre-ablation (PreA), immediate post-ablation (IPA), 24 hours post-ablation (24PA), and first follow-up post-ablation (FPA), which ranged from 4 to 11 weeks post-ablation. Statistical analyses for volume changes between time points and inter-rater reliability were performed. Additionally, comparisons were made between metastatic versus non-metastatic and small versus large lesions in terms of operative parameters and volume changes. RESULTS: There was an acute increase in volume at IPA with a decrease in size by 24PA. ANOVA among inter-rater datasets showed no significant difference at any time point (highest F(1,15) = 0.225, P > 0.80, for IPA). GLM repeated measures, for Intra-Rater analysis, demonstrated statistically significant differences across time points (lowest F(1,15) = 13.297, P = 0.003). IPA volumes were larger than those at PreA, 24PA, and FPA (average volume increase [95% CI]: 281% [157-404%], 167% [134-201%], 187% [154-219%], respectively; all P < 0.004). Correlation analysis showed lower inter-rater reliability at IPA versus other time points (all P < 0.03). Larger lesions (>2.5 cm³ ) versus smaller (<2.5 cm³ ) did not demonstrate a difference in percent volume increase. Operative parameters and volume dynamics were not different between metastatic and non-metastatic groups. CONCLUSIONS: The response of intracranial lesions to LITT demonstrates a peak in volume at the IPA time point with decreased IPA inter-rater reliability. We recommend that conclusions about intracranial lesion size post-LITT be made at least 24 hours post-LITT rather than immediately after LITT.

Deep brain stimulation lead fixation after Stimloc failure.

We report a method for deep brain stimulation (DBS) lead fixation in the event that the primary anchoring device fails to function effectively. The method involves the application of a titanium microplate to secure the lead to the skull, thereby providing a fast and reliable "rescue" mechanism for lead fixation. This method can supplement any burr hole cap and fixation method. Furthermore, this method has several advantages over removal and replacement of the primary anchor, such as a lower possibility of lead migration, faster procedural time, and cost-effectiveness.

Conserved fMRI and LFP signals during new associative learning in the human and macaque monkey medial temporal lobe.

We measured local field potential (LFP) and blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in the medial temporal lobes of monkeys and humans, respectively, as they performed the same conditional motor associative learning task. Parallel analyses were used to examine both data sets. Despite significantly faster learning in humans relative to monkeys, we found equivalent neural signals differentiating new versus highly familiar stimuli, first stimulus presentation, trial outcome, and learning strength in the entorhinal cortex and hippocampus of both species. Thus, the use of parallel behavioral tasks and analyses in monkeys and humans revealed conserved patterns of neural activity across the medial temporal lobe during an associative learning task.

Depth-time interpolation of feature trends extracted from mobile microelectrode data with kernel functions.

BACKGROUND/AIMS: Microelectrode recording (MER) is necessary for precision localization of target structures such as the subthalamic nucleus during deep brain stimulation (DBS) surgery. Attempts to automate this process have produced quantitative temporal trends (feature activity vs. time) extracted from mobile MER data. Our goal was to evaluate computational methods of generating spatial profiles (feature activity vs. depth) from temporal trends that would decouple automated MER localization from the clinical procedure and enhance functional localization in DBS surgery. METHODS: We evaluated two methods of interpolation (standard vs. kernel) that generated spatial profiles from temporal trends. We compared interpolated spatial profiles to true spatial profiles that were calculated with depth windows, using correlation coefficient analysis. RESULTS: Excellent approximation of true spatial profiles is achieved by interpolation. Kernel-interpolated spatial profiles produced superior correlation coefficient values at optimal kernel widths (r = 0.932-0.940) compared to standard interpolation (r = 0.891). The choice of kernel function and kernel width resulted in trade-offs in smoothing and resolution. CONCLUSIONS: Interpolation of feature activity to create spatial profiles from temporal trends is accurate and can standardize and facilitate MER functional localization of subcortical structures. The methods are computationally efficient, enhancing localization without imposing additional constraints on the MER clinical procedure during DBS surgery.

Cohesiveness of spatial and directional representations recorded from neural ensembles in the anterior thalamus, parasubiculum, medial entorhinal cortex, and hippocampus.

Anatomical and physiological evidence suggests that hippocampal place cells derive their spatial firing properties from the medial entorhinal cortex (MEC) and other parahippocampal areas that send spatial and directional input to the MEC. MEC neurons fire in a precise, geometric pattern, forming a hexagonal grid that tessellates the surface of environments. Similar to place cells and head direction cells, the orientation of grid cell firing patterns can be controlled by visual landmarks, but the cells maintain their firing patterns even in the dark. Place cells and head direction cells can also completely decouple from external landmarks in the light, but it is not known whether the MEC and parahippocampal regions exhibit similar properties or are more explicitly tied to external landmarks. We recorded neurons in the MEC, parasubiculum, and CA1 and head direction cells of the anterior thalamus as the rat's internal direction sense was pitted against a salient visual landmark by slowly rotating the rat in a covered bucket while counter-rotating the visual cue. In different sessions, spatial firing rate maps and head direction tuning curves either rotated their preferred firing locations/directions by the same amount as the bucket rotation or maintained their preferences in the external laboratory framework. In few cases, the firing preferences rotated with the cue card. When cells from different regions were recorded simultaneously, the dominant response in one area almost always matched the response of the other areas. Although dominant responses were consistent throughout the recording regions, CA1 ensembles exhibited a greater degree of response heterogeneity than other regions, which nearly all exhibited internally consistent responses. Thus, the parahippocampal and MEC input to the hippocampus can be controlled by the animal's internal direction sense (presumably reflected in the firing of head direction cells) and become completely decoupled from external sensory input, yet maintain internal coherence with each other and in general with the place cell system of the hippocampus.

Hippocampal place cells: parallel input streams, subregional processing, and implications for episodic memory.

The hippocampus is thought to be involved in episodic memory in humans. Place cells of the rat hippocampus offer a potentially important model system to understand episodic memory. However, the difficulties in determining whether rats have episodic memory are profound. Progress can be made by considering the hippocampus as a computational device that presumably performs similar transformations on its inputs in both rats and in humans. Understanding the input/output transformations of rat place cells can thus inform research on the computational basis of human episodic memory. Two examples of different transformations in the CA3 and CA1 regions are presented. In one example, CA3 place fields are shown to maintain a greater degree of population coherence than CA1 place fields after a rearrangement of the salient landmarks in an environment, in agreement with computational models of CA3 as an autoassociative network. In the second example, CA3 place field appears to store information about the spatiotemporal sequences of place fields, starting with the first exposure to a cue-altered environment, whereas CA1 place fields store this information only on a temporary basis. Finally, recordings of hippocampal afferents from the lateral and medial entorhinal cortex (EC) suggest that these two regions convey fundamentally different representations to the hippocampus, with spatial information conveyed by the medial EC and nonspatial information conveyed by the lateral EC. The dentate gyrus and CA3 regions may create configural object+place (or item+context) representations that provide the spatiotemporal context of an episodic memory.

Major dissociation between medial and lateral entorhinal input to dorsal hippocampus.

Hippocampal place cells are a model system of how the brain constructs cognitive representations and of how these representations support complex behavior, learning, and memory. There is, however, a lack of detailed knowledge about the properties of hippocampal afferents. We recorded multiple single units from the hippocampus and the medial and lateral entorhinal areas of behaving rats. Although many medial entorhinal neurons had highly specific place fields, lateral entorhinal neurons displayed weak spatial specificity. This finding demonstrates a fundamental dissociation between the information conveyed to the hippocampus by its major input streams, with spatial information represented by the medial and nonspatial information represented by the lateral entorhinal cortex.