Path Integration Deficits Research Articles

Path integration deficits are associated with phosphorylated tau accumulation in the entorhinal cortex.

Alzheimer's disease is a devastating disease that is accompanied by dementia, and its incidence increases with age. However, no interventions have exhibited clear therapeutic effects. We aimed to develop and characterize behavioural tasks that allow the earlier identification of signs preceding dementia that would facilitate the development of preventative and therapeutic interventions for Alzheimer's disease. To this end, we developed a 3D virtual reality task sensitive to the activity of grid cells in the entorhinal cortex, which is the region that first exhibits neurofibrillary tangles in Alzheimer's disease. We investigated path integration (assessed by error distance) in a spatial navigation task sensitive to grid cells in the entorhinal cortex in 177 volunteers, aged 20-89 years, who did not have self-reported dementia. While place memory was intact even in old age, path integration deteriorated with increasing age. To investigate the relationship between neurofibrillary tangles in the entorhinal cortex and path integration deficit, we examined a mouse model of tauopathy (P301S mutant tau-overexpressing mice; PS19 mice). At 6 months of age, PS19 mice showed a significant accumulation of phosphorylated tau only in the entorhinal cortex, associated with impaired path integration without impairments in spatial cognition. These data are consistent with the idea that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex. This method may allow the early identification of individuals likely to develop Alzheimer's disease.

Early and specific detection of Alzheimer's disease: more than a (virtual) reality?

This scientific commentary refers to 'Path integration deficits are associated with phosphorylated tau accumulation in the entorhinal cortex', by Koike et al. (https://doi.org/10.1093/braincomms/fcad359).

Path integration deficits predict phosphorylated tau accumulation in the entorhinal cortex: Assessment of Braak stage I,II using 3D Virtual reality goggles

AbstractBackgroundWe aimed to develop behavioral tasks that can identify early signs of Alzheimer’s disease (AD) in order to facilitate the development of preventative and therapeutic interventions.MethodTo do this, we created a 3D virtual reality task that is sensitive to the activity of grid cells in the entorhinal cortex, a region that is affected early on in AD. We tested path integration in a spatial navigation task in 177 volunteers between the ages of 20 and 89 who did not have a self‐diagnosed AD.ResultOur results showed that the percentage of subjects showing impaired path integration correlated with the percentage of subjects showing neurofibrillary tangles in the entorhinal cortex, as seen in previously published autopsy data. To further confirm this relationship, we also tested a tauopathy mouse model and found that mice with accumulation of phosphorylated tau in the entorhinal cortex had impaired path integration without impairments in spatial cognition or novel object recognition.ConclusionThese findings suggest that path integration deficit is caused by the accumulation of phosphorylated tau in the entorhinal cortex and may allow for early identification of individuals at risk for developing AD.

Grid cell disruption in a mouse model of early Alzheimer’s disease reflects reduced integration of self-motion cues

Converging evidence from human and rodent studies suggests that disrupted grid cell coding in the medial entorhinal cortex (MEC) underlies path integration behavioral deficits during early Alzheimer's disease (AD). However, grid cell firing relies on both self-motion cues and environmental features, and it remains unclear whether disrupted grid coding can account for specific path integration deficits reported during early AD. Here, we report in the J20 transgenic amyloid beta (Aβ) mouse model of early AD that grid cells were spatially unstable toward the center of the arena, had qualitatively different spatial components that aligned parallel to the borders of the environment, and exhibited impaired integration of distance traveled via reduced theta phase precession. Our results suggest that disrupted early AD grid coding reflects reduced integration of self-motion cues but not environmental information via geometric boundaries, providing evidence that grid cell impairments underlie path integration deficits during early AD.

Wayfinding and path integration deficits detected using a virtual reality mobile app in patients with traumatic brain injury.

The ability to navigate is supported by a wide network of brain areas which are particularly vulnerable to disruption brain injury, including traumatic brain injury (TBI). Wayfinding and the ability to orient back to the direction you have recently come (path integration) may likely be impacted in daily life but have so far not been tested with patients with TBI. Here, we assessed spatial navigation in thirty-eight participants, fifteen of whom had a history of TBI, and twenty-three control participants. Self-estimated spatial navigation ability was assessed using the Santa Barbara Sense of Direction (SBSOD) scale. No significant difference between TBI patients and a control group was identified. Rather, results indicated that both participant groups demonstrated 'good' self-inferred spatial navigational ability on the SBSOD scale. Objective navigation ability was tested via the virtual mobile app test Sea Hero Quest (SHQ), which has been shown to predict real-world navigation difficulties and assesses (a) wayfinding across several environments and (b) path integration. Compared to a sub-sample of 13 control participants, a matched subsample of 10 TBI patients demonstrated generally poorer performance on all wayfinding environments tested. Further analysis revealed that TBI participants consistently spent a shorter duration viewing a map prior to navigating to goals. Patients showed mixed performance on the path integration task, with poor performance evident when proximal cues were absent. Our results provide preliminary evidence that TBI impacts both wayfinding and, to some extent, path integration. The findings suggest long-lasting clinical difficulties experienced in TBI patients affect both wayfinding and to some degree path integration ability.

Chronic stress is associated with specific path integration deficits

Repeated exposure to stress (chronic stress) can cause excess levels of circulating cortisol and has detrimental influences on various cognitive functions including long-term memory and navigation. However, it remains an open question whether chronic stress affects path integration, a navigational strategy that presumably relies on the functioning of grid cells in the medial entorhinal cortex. The entorhinal cortex is a brain region in the medial temporal lobe, which contains multiple cell types involved in spatial navigation (and episodic memory), and a high number of corticosteroid receptors, predisposing it as a potential target of cortisol effects. Here, our goal was to investigate the association between chronic stress and path integration performance. We assessed chronic stress via hair cortisol concentration (physiological measure) and the Perceived Stress Questionnaire (subjective measure) in 52 female participants aged 22–65 years. Path integration was measured using a virtual homing task. Linear mixed models revealed selective impairments associated with chronic stress that depended on error type and environmental features. When focusing on distance estimations in the path integration task, we observed a significant relationship to hair cortisol concentrations indicating impaired path integration particularly during trials with higher difficulty in participants with high hair cortisol concentrations. This relationship especially emerged in the absence of spatial cues (a boundary or a landmark), and particularly in participants who reported high levels of subjectively experienced chronic stress. The findings are in line with the hypothesis that chronic stress compromises path integration, possibly via an effect on the entorhinal grid cell system.

Vestibular contribution to path integration deficits in 'at-genetic-risk' for Alzheimer's disease.

Path integration changes may precede a clinical presentation of Alzheimer's disease by several years. Studies to date have focused on how spatial cell changes affect path integration in preclinical AD. However, vestibular input is also critical for intact path integration. Here, we developed the vestibular rotation task that requires individuals to manually point an iPad device in the direction of their starting point following rotational movement, without any visual cues. Vestibular features were derived from the sensor data using feature selection. Machine learning models illustrate that the vestibular features accurately classified Apolipoprotein E ε3ε4 carriers and ε3ε3 carrier controls (mean age 62.7 years), with 65% to 79% accuracy depending on task trial. All machine learning models produced a similar classification accuracy. Our results demonstrate the cross-sectional role of the vestibular system in Alzheimer's disease risk carriers. Future investigations should examine if vestibular functions explain individual phenotypic heterogeneity in path integration among Alzheimer's disease risk carriers.

Using an entorhinal cortex‐based virtual reality navigation task to differentiate between individuals with and without subjective cognitive decline

AbstractBackgroundEntorhinal cortex is vulnerable to neurodegenerative changes in the earliest stages of AD. However, this early AD stage cannot be detected by currently available neuropsychological tests. The entorhinal cortex contains spatial modulated cells, known as grid cells, that play a key role in supporting path integration (PI), a crucial component of spatial navigation that supports continuous integration of self‐motion information and in combination with environmental cues provides accurate internal representation of space. Previously, PI deficits were associaed with impaired grid cell function in healthy older adults and in young APOE‐E4 carriers. Importantly, PI performance has successfully discriminated between biomarker positive and negative mild cognitive impairment patients and between healthy older adults at higher and lower risk of AD. In this study, we tested whether performance on an immersive virtual reality PI task can differentiate between patients with and without subjective cognitive decline (SCD).MethodA group of healthy older adults and SCD patients will perform an immersive virtual reality PI task. In this task, participants are immersed in an open‐field virtual environment and are guided along short, curved paths. At certain points they are asked to stop and indicate their initial heading orientation and the location of an object, providing information about distance and orientation coding. During the task participants have access to multisensory self‐motion cues (visual, vestibular and proprioceptive), all of which are pivotal for supporting grid cell function. Additionally, participants will be screened for presence of objective cognitive impairments and will undergo an assessment of their visuospatial working memory and balance.ResultWe will compare if SCD patients perform worse than healthy older controls in the general PI performance measures (e.g., PI error, response time). Furthermore, we will apply a recently developed computational model to identify multiple sources of PI error. This approach allows for a very nuanced characterization of PI deficits, and, as a result, provides additional, potentially even more sensitive markers of very early AD compared to typical PI performance measures.ConclusionThe results will be discussed with reference to the utility of immersive virtual PI as a sensitive biomarker for early, preclinical, AD manifestation.

Path integration in normal aging and Alzheimer's disease.

In this review we discuss converging evidence from human and rodent research demonstrating how path integration (PI) is impaired in healthy aging and Alzheimer's disease (AD), and point to the neural mechanisms that underlie these deficits. Importantly, we highlight that (i) the grid cell network in the entorhinal cortex is crucial for PI in both humans and rodents, (ii) PI deficits are present in healthy aging and are significantly more pronounced in patients with early-stage AD, (iii) compromised entorhinal grid cell computations in healthy older adults and in young adults at risk of AD are linked to PI deficits, and (iv) PI and grid cell deficits may serve as sensitive markers for pathological decline in early AD.

Path integration changes as a cognitive biomarker for vascular cognitive impairment? A pilot study

AbstractBackgroundPath integration spatial navigation processes are emerging as promising cognitive biomarkers for prodromal and clinical Alzheimer’s disease (AD). However, such path integration changes have been little explored in Vascular Cognitive Impairment (VCI),despite neurovascular change being a major contributing factor to dementia and potentially AD. In particular, the sensitivity and specificity of path integration impairments in VCI compared to AD is unclear. In the current pilot study, we explore path integration performance in AD and VCI patient groups and hypothesise that i) medial parietal mediated egocentric processes will be more affected in VCI and ii) medial temporal mediated allocentric processes will be more affected in AD.MethodThe cross‐sectional study included early stage VCI patients (n=9), AD patients (n=10) and healthy age‐matched controls (n=20). All participants underwent extensive neuropsychological testing, as well as spatial navigation testing. The spatial navigation tests included the virtual reality ‘Supermarket’ task assessing egocentric (body‐based) and allocentric (map‐based) navigation as well as the ‘Clock Orientation’ test assessing egocentric and path integration processes.ResultFindings showed that egocentric path integration processes are only impaired in VCI, potentially distinguishing it from AD. Whereas, allocentric path integration was similarly impaired for VCI and AD. Egocentric scores of Supermarket and Clock Orientation predictors explained 77% (Nagelkerke R 2 ) of variance in VCI and AD patients and correctly classified 84% of patients (7 out of 9 VCI; 9 out of 10 AD) into their respective cohorts. ROC curves were computed and similarly, Area Under the Curve (AUC) values indicated that egocentric orientation in the Supermarket (AUC = .8, SE = .12; 95% CI [.56, 1]) and Clock test (AUC= .91, SE = .06, 95% CI [.8, 1]) had strong diagnostic accuracy in distinguishing VCI from AD patients.ConclusionThese preliminary findings suggest egocentric path integration deficits emerge as more specific to VCI, potentially allowing for more specific diagnostic and treatment outcome measures for vascular impairment in dementia. By contrast, there was limited specificity of allocentric path integration deficits between VCI and AD.

Unmasking selective path integration deficits in Alzheimer's disease risk carriers.

Alzheimer's disease (AD) manifests with progressive memory loss and spatial disorientation. Neuropathological studies suggest early AD pathology in the entorhinal cortex (EC) of young adults at genetic risk for AD (APOE ε4-carriers). Because the EC harbors grid cells, a likely neural substrate of path integration (PI), we examined PI performance in APOE ε4-carriers during a virtual navigation task. We report a selective impairment in APOE ε4-carriers specifically when recruitment of compensatory navigational strategies via supportive spatial cues was disabled. A separate fMRI study revealed that PI performance was associated with the strength of entorhinal grid-like representations when no compensatory strategies were available, suggesting grid cell dysfunction as a mechanistic explanation for PI deficits in APOE ε4-carriers. Furthermore, posterior cingulate/retrosplenial cortex was involved in the recruitment of compensatory navigational strategies via supportive spatial cues. Our results provide evidence for selective PI deficits in AD risk carriers, decades before potential disease onset.

Path Integration Changes as a Cognitive Marker for Vascular Cognitive Impairment?-A Pilot Study.

Path integration spatial navigation processes are emerging as promising cognitive markers for prodromal and clinical Alzheimer’s disease (AD). However, such path integration changes have been less explored in Vascular Cognitive Impairment (VCI), despite neurovascular change being a major contributing factor to dementia and potentially AD. In particular, the sensitivity and specificity of path integration impairments in VCI compared to AD is unclear. In the current pilot study, we explore path integration performance in early-stage AD and VCI patient groups and hypothesize that: (i) medial parietal mediated egocentric processes will be more affected in VCI; and (ii) medial temporal mediated allocentric processes will be more affected in AD. This cross-sectional study included early-stage VCI patients (n = 9), AD patients (n = 10) and healthy age-matched controls (n = 20). All participants underwent extensive neuropsychological testing, as well as spatial navigation testing. The spatial navigation tests included the virtual reality “Supermarket” task assessing egocentric (body-based) and allocentric (map-based) navigation as well as the “Clock Orientation” test assessing egocentric and path integration processes. Results showed that egocentric integration processes are only impaired in VCI, potentially distinguishing it from AD. However, in contrast to our prediction, allocentric integration was not more impaired in AD compared to VCI. These preliminary findings suggest limited specificity of allocentric integration deficits between VCI and AD. By contrast, egocentric path integration deficits emerge as more specific to VCI, potentially allowing for more specific diagnostic and treatment outcome measures for vascular impairment in dementia.

Compromised Grid-Cell-like Representations in Old Age as a Key Mechanism to Explain Age-Related Navigational Deficits

SummaryA progressive loss of navigational abilities in old age has been observed in numerous studies, but we have only limited understanding of the neural mechanisms underlying this decline [1]. A central component of the brain’s navigation circuit are grid cells in entorhinal cortex [2], largely thought to support intrinsic self-motion-related computations, such as path integration (i.e., keeping track of one’s position by integrating self-motion cues) [3, 4, 5, 6]. Given that entorhinal cortex is particularly vulnerable to neurodegenerative processes during aging and Alzheimer’s disease [7, 8, 9, 10, 11, 12, 13, 14], deficits in grid cell function could be a key mechanism to explain age-related navigational decline. To test this hypothesis, we conducted two experiments in healthy young and older adults. First, in an fMRI experiment, we found significantly reduced grid-cell-like representations in entorhinal cortex of older adults. Second, in a behavioral path integration experiment, older adults showed deficits in computations of self-position during path integration based on body-based or visual self-motion cues. Most strikingly, we found that these path integration deficits in older adults could be explained by their individual magnitudes of grid-cell-like representations, as reduced grid-cell-like representations were associated with larger path integration errors. Together, these results show that grid-cell-like representations in entorhinal cortex are compromised in healthy aging. Furthermore, the association between grid-cell-like representations and path integration performance in old age supports the notion that grid cells underlie path integration processes. We therefore conclude that impaired grid cell function may play a key role in age-related decline of specific higher-order cognitive functions, such as spatial navigation.

Acetylcholine contributes to the integration of self-movement cues in head direction cells.

Acetylcholine contributes to accurate performance on some navigational tasks, but details of its contribution to the underlying brain signals are not fully understood. The medial septal area provides widespread cholinergic input to various brain regions, but selective damage to medial septal cholinergic neurons generally has little effect on landmark-based navigation, or the underlying neural representations of location and directional heading in visual environments. In contrast, the loss of medial septal cholinergic neurons disrupts navigation based on path integration, but no studies have tested whether these path integration deficits are associated with disrupted head direction (HD) cell activity. Therefore, we evaluated HD cell responses to visual cue rotations in a familiar arena, and during navigation between familiar and novel arenas, after muscarinic receptor blockade with systemic atropine. Atropine treatment reduced the peak firing rate of HD cells, but failed to significantly affect other HD cell firing properties. Atropine also failed to significantly disrupt the dominant landmark control of the HD signal, even though we used a procedure that challenged this landmark control. In contrast, atropine disrupted HD cell stability during navigation between familiar and novel arenas, where path integration normally maintains a consistent HD cell signal across arenas. These results suggest that acetylcholine contributes to path integration, in part, by facilitating the use of idiothetic cues to maintain a consistent representation of directional heading. (PsycINFO Database Record

Linear Path Integration Deficits in Patients with Abnormal Vestibular Afference

Effective navigation requires the ability to keep track of one's location and maintain orientation during linear and angular displacements. Path integration is the process of updating the representation of body position by integrating internally-generated self-motion signals over time (e.g., walking in the dark). One major source of input to path integration is vestibular afference. We tested patients with reduced vestibular function (unilateral vestibular hypofunction, UVH), patients with aberrant vestibular function (benign paroxysmal positional vertigo, BPPV), and healthy participants (controls) on two linear path integration tasks: experimenter-guided walking and target-directed walking. The experimenter-guided walking task revealed a systematic underestimation of self-motion signals in UVH patients compared to the other groups. However, we did not find any difference in the distance walked between the UVH group and the control group for the target-directed walking task. Results from neuropsychological testing and clinical balance measures suggest that the errors in experimenter-guided walking were not attributable to cognitive and/or balance impairments. We conclude that impairment in linear path integration in UVH patients stem from deficits in self-motion perception. Importantly, our results also suggest that patients with a UVH deficit do not lose their ability to walk accurately without vision to a memorized target location.

Walking speed and vestibular disorders in a path integration task

The goal of this study was to determine if parameters of gait are related to the path integration deficits in some people with vestibular disorders. We tested normals, and two groups of vestibularly impaired people, with unilateral benign paroxysmal positional vertigo and with unilateral weakness. Each group had 20 subjects. They walked straight ahead for 7.62m, with eyes open or closed, to the beat of a metronome at 60 beats/min, 120 beats/min and 176 beats/min. When adjusted for age and sex, normals veered significantly less and walked significantly further before veering than the unilateral weakness group; all groups veered significantly less at 120 beats/min than the slower or faster cadences. Older patients walked slightly but significantly slower than younger patients at the faster speeds. Step length did not differ among diagnostic groups. These data confirm the involvement of vestibular function in path integration, suggest a differentiation by type of vestibular impairment, and suggest some differences by cadence.

(±)-3,4-Methylenedioxymethamphetamine treatment in adult rats impairs path integration learning: A comparison of single vs once per week treatment for 5 weeks

3,4-Methlylenedioxymethamphetamine (MDMA) administration (4 × 15 mg/kg) on a single day has been shown to cause path integration deficits in rats. While most animal experiments focus on single binge-type models of MDMA use, many MDMA users take the drug on a recurring basis. The purpose of this study was to compare the effects of repeated single-day treatments with MDMA (4 × 15 mg/kg) once weekly for 5 weeks to animals that only received MDMA on week 5 and saline on weeks 1–4. In animals treated with MDMA for 5 weeks, there was an increase in time spent in the open area of the elevated zero maze suggesting a decrease in anxiety or increase in impulsivity compared to the animals given MDMA for 1 week and saline treated controls. Regardless of dosing regimen, MDMA treatment produced path integration deficits as evidenced by an increase in latency to find the goal in the Cincinnati water maze. Animals treated with MDMA also showed a transient hypoactivity that was not present when the animals were re-tested at the end of cognitive testing. In addition, both MDMA-treated groups showed comparable hyperactive responses to a later methamphetamine challenge. No differences were observed in spatial learning in the Morris water maze during acquisition or reversal but MDMA-related deficits were seen on reduced platform-size trials. Taken together, the data show that a single-day regimen of MDMA induces deficits similar to that of multiple weekly treatments.

Treatment with MDMA from P11–20 disrupts spatial learning and path integration learning in adolescent rats but only spatial learning in older rats

Previous studies in rats showed that postnatal day (P)11-20 exposure to +/-3,4-methylenedioxymethamphetamine (MDMA, ecstasy) causes learning and memory deficits in adulthood. The emergence and permanence of these learning deficits are currently unknown. This study was designed to investigate learning and memory deficits in adolescent (P30 or P40) and older (P180 or P360) rats exposed to MDMA from P11-20. Within each litter half the animals were exposed to MDMA (20 mg/kg) and half to saline (SAL) twice a day (8 h apart) from P11-20. In experiment (exp) 1, behavioral testing began on either P30 or P40, whereas in exp 2, testing began on either P180 or P360. Offspring were tested in the Cincinnati water maze (CWM), a test of path integration learning (2 trials/day for 5 days), and the Morris water maze (MWM) (three phases, with 5 days of 4 trials/day and a probe trial on the sixth day per phase). MDMA-treated rats took longer to find the platform and traveled a greater distance to find the platform at all ages tested in all phases of the MWM. MDMA-treated animals also spent less time in the target quadrant during probe trials. In the CWM, P30 and P40 animals took longer to find the goal and committed more errors in locating the goal, while P180 and P360 MDMA-treated animals performed similarly to SAL-treated animals. The data suggest that the spatial learning and memory deficits induced by MDMA are long lasting, while the path integration deficits recover over time.

Comparison of monoamine and corticosterone levels 24 h following (+)methamphetamine, (+/–)3,4‐methylenedioxymethamphetamine, cocaine, (+)fenfluramine or (+/–)methylphenidate administration in the neonatal rat

We have previously shown that neonatal administration of (+/-)3,4-methylenedioxymethamphetamine and (+)fenfluramine produce deficits in spatial and path integration learning, whereas (+)methamphetamine causes deficits in spatial learning. Conversely, cocaine and (+/-)methylphenidate have no effect on either form of learning following neonatal administration. The purpose of the present study was to determine whether corticosterone and/or monoamine levels were changed following subcutaneous administration of 10 mg/kg (+)methamphetamine, (+/-)3,4-methylenedioxymethamphetamine, (+)fenfluramine, (+/-)methylphenidate or cocaine every 2 h (total of four injections) on postnatal day 11. Twenty-four hours after the first dose, plasma, striatum and hippocampus were collected. Corticosterone levels were increased in methamphetamine-, fenfluramine-, methylenedioxymethamphetamine- and methylphenidate-treated rats relative to levels in saline-treated rats, whereas cocaine-treated rats were unaffected. In the striatum and hippocampus, serotonin and 5-hydroxyindolacetic acid were reduced in animals treated with methylenedioxymethamphetamine or fenfluramine, compared with levels in saline controls. Dopamine levels were not changed by any of the drugs, although 3,4-dihydroxyphenylacetic acid was decreased following methylenedioxymethamphetamine or methamphetamine. Minimal effects were seen in neurotransmitter levels following injection of cocaine or methylphenidate. These data suggest that drugs that affect corticosterone and hippocampal serotonin are associated with both spatial learning and path integration deficits, and those that affect corticosterone and 3,4-dihydroxyphenylacetic acid are associated with spatial learning deficits only.

Disorientation combined with bilateral parietal cortex lesions causes path integration deficits in the water maze

The navigational abilities of rats were examined using the water maze after disorientation induced by rotation and/or swimming in darkness. Control and light-disoriented groups performed similarly, whereas the dark group and the dark-disoriented groups were initially much slower but improved to control levels. After receiving bilateral parietal lesions, multiple start position tests showed that both rotation groups were severely impaired in finding the hidden platform. The effects of disorientation induced by darkness and by rotation are therefore separable.