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Examining hippocampal function in schizophrenia using a virtual reality spatial navigation task
... Naturally, VR is also used in rehabilitation and neuroimaging proves to be particularly useful in combination with VR in these cases (Ansado et al., 2020). VR-fMRI is even used to study specific features of pathologies, such as freezing of gait in Parkinson's disease (for recent reviews, see Bluett et al. (2019) and Gilat et al. (2019)), spatial learning in bulimia nervosa (Cyr et al., 2016) and in schizophrenia (Salgado-Pineda et al., 2016), or fear learning for post-traumatic stress disorder (PTSD) (for a review see Glenn et al. (2018)). Some interesting points have already been highlighted thanks to VR, for example grid-cell-like representations in spatial cognition in human beings (Doeller et al., 2010); however, there is no standard solution for the VR-fMRI combination. ...
... The first possibility is to define onsets, for instance when an active trigger signal is sent by the MRI before the start of each scan (Beck et al., 2010). Another option is to acquire fMRI data in blocks (see for instance Adamovich et al. (2009), Mueller et al. (2012, Salgado-Pineda et al. (2016) or Modroño et al. (2019)). Lastly, it is possible to continuously acquire data. ...
... Age means and ranges varied between experiments, and sometimes age information (Burgess et al., 2001;Demanuele et al., 2015;Nau et al., 2020) or gender distribution information was missing. Participants were mostly healthy, though we counted one study with a group of bulimia nervosa patients (Cyr et al., 2016), one study with ketamine users (Morgan et al., 2014), two studies with schizophrenia patients (Salgado-Pineda et al., 2016;Siemerkus et al., 2012), one study with athletes with mild traumatic brain injuries (Slobounov et al., 2010), one study with cocaine dependent patients (Tau et al., 2014), and one study with patients with childhood abuse (Weniger et al., 2013). However, all these studies included one matching healthy control group. ...
Virtual Reality (VR) is an increasingly widespread tool for research as it allows the creation of experiments taking place in multimodal and daily-life-like environments, while keeping a strong experimental control. Adding neuroimaging to VR leads to a better understanding of the underlying brain networks activated during a naturalistic task, whether for research purposes or rehabilitation. The present paper focuses on the specific use of concurrent VR and fMRI and its technical challenges and feasibility, with a brief examination of the general existing solutions. Following the PRISMA guidelines, the review investigates the particular case of how VR-fMRI has explored episodic memory so far, with a comparison of object- and place-based episodic memory. This review confirms the involvement of cerebral regions well-known to be implicated in episodic memory and unravels other regions devoted to bodily and narrative aspects of the self, promoting new avenues of research in the domain of naturalistic episodic memory. Future studies should develop more immersive and interactive virtual neuroimaging features to increase ecological and embodied neurocognition aspects.
... Virtual Reality Town [107] represents a virtual city in which most of the buildings are grey and undefined. Further, there are 25 strategically placed colored structures: a bank, a bakery, a cinema, telephone box, etc., which serve as cues for navigation. ...
... These studies rely on virtual reality environments that embed cognitive tasks targeted at particular cognitive abilities. The virtual environments try to depict realistic environments: car driving in a city [30,107], an apartment [60,110,111,66], a furniture storage unit [68], a building [41] [98], a bungalow [69], a classroom [80,15,83,84], a library [132], a supermarket [89,106,97], an office [92], a kitchen [108], and even a military vehicle [16]. ...
... For example, digital tests mitigate the bias consequence of the educational or cultural level with the reproduction of tasks closely resembling everyday life situations, but new confounding factors may appear such as a technological gap. To address this issue, some papers adapt task difficulty according to participants' characteristics, taking into account the number of stimuli or their presentation speed, both direct and distractors [65,135]; the type of navigation that can perform the user (e.g., active or passive) [16,107,114]; or the interface or device used, among the most relevant aspects. Other works address the compensation of confounding factors at the data analytics stage [78,79], typically through the correlation with the classic tests in which they rely. ...
Background:
The dramatic technological advances witnessed in recent years have resulted in a great opportunity for changing the way neuropsychological evaluations may be performed in clinical practice. Particularly, serious games have been posed as the cornerstone of this still incipient paradigm-shift, as they have characteristics that make them especially advantageous in trying to overcome limitations associated with traditional pen-and-paper based neuropsychological tests: they can be easily administered and they can feature complex environments for the evaluation of neuropsychological constructs that are difficult to evaluate through traditional tests. The objective of this study was to conduct a scoping literature review in order to map rapidly the key concepts underpinning this research area during the last 25 years on the use of serious games for neuropsychological evaluation.
Methods:
MEDLINE, PsycINFO, Scopus and IEEE Xplore databases were systematically searched. The main eligibility criteria were to select studies published in a peer-reviewed journal; written in English; published in the last 25 years; focused on the human population, and classified in the neuropsychological field. Moreover, to avoid risk of bias, studies were selected by consensus of experts, focusing primarily in psychometric properties. Therefore, selected studies were analyzed in accordance with a set of dimensions of analysis commonly used for evaluating neuropsychological tests.
Results:
After applying the selected search strategy, 57 studies -including 54 serious games- met our selection criteria. The selected studies deal with visuospatial capabilities, memory, attention, executive functions, and complex neuropsychological constructs such as Mild Cognitive Impairment (MCI). Results show that the implementation of serious games for neuropsychological evaluation is tackled in several different ways in the selected studies, and that studies have so far been mainly exploratory, just aiming at testing the feasibility of the proposed approaches.
Discussion:
It may be argued that the limited number of databases used might compromise this study. However, we think that the finally included sample is representative, in spite of how difficult is to achieve an optimum and maximum scope. Indeed, this review identifies other research issues related to the development of serious games beyond their reliability and validity. The main conclusion of this review is that there is a great interest in the research community in the use of serious games for neuropsychological evaluation. This scoping review is pertinent, in accordance with the increasing number of studies published in the last three years, they demonstrate its potential as a serious alternative to classic neuropsychological tests. Nevertheless, more research is needed in order to implement serious games that are reliable, valid, and ready to be used in the everyday clinical practice.
... It has been revealed that spatial navigation is associated with activation of parahippocampal gyrus, posterior hippocampus, striatum (caudate nucleus), the parietal and temporal lobes, and the prefrontal and retrosplenial cortices (Aguirre et al., 1996;Boccia et al., 2014;Bohbot et al., 1998;Burgess et al., 2001;Grön et al., 2000;Hartley et al., 2003;Iaria et al., 2003;Iglói et al., 2010;Maguire et al., 1997;Marsh et al., 2010;Mohammadi et al., 2018aMohammadi et al., , 2018bOrban et al., 2006;Parslow et al., 2004;Peigneux et al., 2004;Rasetti et al., 2014;Rauchs et al., 2008;Shipman and Astur, 2008;Weniger and Irle, 2006;Xu et al., 2010). Interestingly, the reduced activation of the left occipital/temporal cortex and the left dorsolateral prefrontal cortex (DLPFC) during spatial navigation have been reported in the subjects with schizophrenia (Salgado-Pineda et al., 2016). Likewise, the reduced activation in the parahippocampal gyrus have been shown in the patients with schizophrenic. ...
... working memory performance and supported the hypothesis that irregular PFC responses arose from abnormal PFC neurons (Callicott et al., 2000). Consistent with the results of Callicott et al. (2000)and Salgado-Pineda et al.(2016), it seems that the defect in spatial navigation in patients with schizoaffective disorder and schizophrenia is likely to be due to damage to DLPFC. This is the first study to directly compare the allocentric and egocentric memories in patients with schizoaffective disorder and schizophrenia in a virtual neighbourhood with lots of navigational landmarks and in a virtual maze with no topographical landmarks. ...
Dysfunction of allocentric and egocentric memories is one of the core features of psychiatric disorders. There are a few navigational studies on these memories in schizophrenia and bipolar disorders, but studies in schizoaffective disorder are lacking. Here, we aim to explore allocentric and egocentric navigation deficits in these subjects using our advanced recently developed virtual reality navigation task (VRNT). Twenty patients with schizophrenia and 20 with schizoaffective disorder were compared with 20 normal volunteer subjects on VRNTs consisting of a virtual neighbourhood (allocentric memory) and a virtual maze (egocentric memory). Compared with schizoaffective disorder and control subjects, patients with schizophrenia had the worst performance on both virtual neighbourhood and virtual maze tasks. The allocentric memory in both patients with schizophrenia and those with schizoaffective disorder was more impaired than the egocentric memory (p˂0.001). However, the patients with schizoaffective disorder performed better in egocentric memory than those with schizophrenia, as they had fewer errors in the virtual maze. It was concluded that allocentric memory is more impaired than egocentric in both schizoaffective disorder and schizophrenia patients, whereas patients with schizoaffective disorder performed better in egocentric memory than patients with schizophrenia. It was also concluded that allocentric memory deficits can help differentiate patients with schizophrenia and schizoaffective disorder from healthy participants, whereas egocentric memory deficits can be used to distinguish them from each other.
... Future research should be based on paradigms that allow the use of VR assessment of executive functioning with methods of functional neuroimaging. This approach has been already used in research on memory, learning, language production and comprehension, and social interaction (with the use of functional brain neuroimaging, e.g., [126,[152][153][154][155] and with event-related potentials based on electroencephalography, e.g., [156,157]). Gainsford et al. [158] made the interesting proposal of combining VR methods with non-invasive brain stimulation in the social cognition domain, which would also be interesting to use to investigate executive function in schizophrenia. ...
In recent years, interest has grown in measuring executive function in schizophrenia with ecological and virtual reality (VR) tools. However, there is a lack of critical analysis comparing those tools with traditional ones. This paper aims to characterize executive dysfunction in schizophrenia by comparing ecological and virtual reality assessments with traditional tools, and to describe the neurobiological and psychopathological correlates. The analysis revealed that ecological and VR tests have higher levels of verisimilitude and similar levels of veridicality compared to traditional tools. Both negative symptoms and disorganization correlate significantly with executive dysfunction as measured by traditional tools, but their relationships with measures based on ecological and VR methods are still unclear. Although there is much research on brain correlates of executive impairments in schizophrenia with traditional tools, it is uncertain if these results will be confirmed with the use of ecological and VR tools. In the diagnosis of executive dysfunction, it is important to use a variety of neuropsychological methods—especially those with confirmed ecological validity—to properly recognize the underlying characteristics of the observed deficits and to implement effective forms of therapy.
... In rodent models, adult-born hippocampal neurons have been shown to be involved in a number of behavioural processes, spanning pattern separation 16,17 , spatial navigation 18,19 , memory turnover 20 , and acquisition 21 and extinction 22 of fear memory. There behaviours are affected in psychiatric disorders including schizophrenia [23][24][25][26] . Antipsychotic drugs, specifically atypical antipsychotics, also impact AHN 27 and importantly, a number of functionally diverse schizophrenia risk genes, including DISC1 28 , SREB2/GPR85 29 , CACNA1C 30,31 DGCR8 32 and miR137 33 , converge in their ability to modify AHN. ...
Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.
... Standard EEG systems combined with VR have also been used to explore the relevance of theta oscillations during spatial navigation in humans (Boulanger et al. 2004;Sharma et al. 2017). Functional magnetic resonance imaging (fMRI) has been used to explore brain region activations during virtual spatial navigation, with focus on recognition and strategy selection Salgado-Pineda et al. 2016). However, these systems must be stationary, which may reduce immersive properties of some VR systems. ...
The ability to accurately recall locations and navigate our environment relies on multiple cognitive mechanisms. The behavioural and neural correlates of spatial navigation have been repeatedly examined using different types of mazes and tasks with animals. Accurate performances of many of these tasks have proven to depend on specific circuits and brain structures and some have become the standard test of memory in many disease models. With the introduction of virtual reality (VR) to neuroscience research, VR tasks have become a popular method of examining human spatial memory and navigation. However, the types of VR tasks used to examine navigation across laboratories appears to greatly differ, from open arena mazes and virtual towns to driving simulators. Here, we examined over 200 VR navigation papers, and found that the most popular task used is the virtual analogue of the Morris water maze (VWM). Although we highlight the many advantages of using the VWM task, there are also some major difficulties related to the widespread use of this behavioural method. Despite the task's popularity, we demonstrate an inconsistency of use - particularly with respect to the environmental setup and procedures. Using different versions of the virtual water maze makes replication of findings and comparison of results across researchers very difficult. We suggest the need for protocol and design standardisation, alongside other difficulties that need to be addressed, if the virtual water maze is to become the 'gold standard' for human spatial research similar to its animal counterpart.
... Some digital technologies, called virtual realities, are capable of giving their users the impression that they are inside a simulated space. These technologies could be widely used for research purposes to investigate the mechanisms of abnormal rationality because they allow us to assess patients' behavior in particular environments, to provoke symptoms if their trigger is known and to measure symptom severity (Bekele et al., 2017;Canty et al., 2017;Han et al., 2014;Hesse et al., 2017;Mohammadi et al., 2018;Salgado-Pineda et al., 2016;van Bennekom et al., 2017). The clinical implementation of virtual/augmented reality (VR/AR) technologies in psychiatry and psychotherapy aims to teach patients coping skills that can be transferred from a virtual environment to their daily life. ...
While the implementation of digital technology in psychiatry appears promising, there is an urgent need to address the implications of the absence of ethical design in the early development of such technologies. Some authors have noted the gap between technology development and ethical analysis and have called for an upstream examination of the ethical issues raised by digital technologies. In this paper, we address this suggestion, particularly in relation to digital healthcare technologies for patients with schizophrenia spectrum disorders. The introduction of digital technologies in psychiatry offers a broad spectrum of diagnostic and treatment options tailored to the health needs and goals of patients’ care. These technologies include wearable devices, smartphone applications for high-immersive virtual realities, smart homes, telepsychiatry and messaging systems for patients in rural areas. The availability of these technologies could increase access to mental health services and improve the diagnostics of mental disorders.
Additional Instruction Abstract
In this descriptive review, we systematize ethical concerns about digital technologies for mental health with a particular focus on individuals suffering from schizophrenia. There are many unsolved dilemmas and conflicts of interest in the implementation of these technologies, such as (1) the lack of evidence on efficacy and impact on self-perception; (2) the lack of clear standards for the safety of their daily implementation; (3) unclear roles of technology and a shift in the responsibilities of all parties; (4) no guarantee of data confidentiality; and (5) the lack of a user-centered design that meets the particular needs of patients with schizophrenia. mHealth can improve care in psychiatry and make mental healthcare services more efficient and personalized while destigmatizing mental health disorders. To ensure that these technologies will benefit people with mental health disorders, we need to heighten sensitivity to ethical issues among mental healthcare specialists, health policy makers, software developers, patients themselves and their proxies. Additionally, we need to develop frameworks for furthering sustainable development in the digital technologies industry and for the responsible usage of such technologies for patients with schizophrenia in the clinical setting. We suggest that digital technology in psychiatry, particularly for schizophrenia and other serious mental health disorders, should be integrated into treatment with professional supervision rather than as a self-treatment tool.
... Several lines of evidence have implicated the hippocampus, a brain region crucial for memory and cognitive processing, in the pathophysiology of schizophrenia (Harrison, 2004). Neuroimaging studies have indicated that individuals with schizophrenia show abnormal brain structure and cellular function (Heckers, 2001;Haijma et al., 2013;Salgado-Pineda et al., 2016;Nakahara et al., 2018), including a reorganization of glutamatergic receptors and altered downstream activation of signaling cascades (Clinton and Meadow-Woodruff, 2004;Hahn et al., 2006;Kristiansen et al., 2006). ...
Please cite this article as: M. Hernández-Frausto, C. López-Rubalcava and E.J. Galván, Progressive Alterations in Synaptic Transmission and Plasticity of Area CA1 Precedes the Cognitive Impairment Associated with Neonatal Administration of MK-801, Neuroscience, https://doi. Abstract Transient hypofunction of NMDA receptors during brain maturation has been linked to cellular and behavioral alterations that mirror symptoms of schizophrenia. In line with this notion, neonatal administration of the non-competitive NMDA receptor antagonist, MK-801, mimics the negative and cognitive symptoms of schizophrenia. By combining behavioral evaluations with extracellular recordings in acute hippocampal slices, we uncovered a progressive alteration of synaptic transmission of animals neonatally treated with MK-801. During the periadolescent stage (up to postnatal day 30), before any behavioral alterations were observed, the synaptic transmission of hippocampal area CA1 exhibited progressive signs of alteration, such as the reduction in synaptic strength and impairment of short-and long-term forms of synaptic plasticity. As expected, behavioral impairments were consistently observed during the young adult stage (postnatal day 90), a period in which a steady deterioration of long-term depression and long-term potentiation was observed. Taken together, these results suggest that synaptic dysregulation precedes behavioral deterioration in a model that mimics the negative and cognitive symptoms of schizophrenia.
... These tasks are thought to test mainly the the goal/active maintenance and flexible updating working memory subdomains (Table 2). Topographical disorientation and disturbances of egocentric topographical working memory are well described problems in AD (Bird et al., 2010;Mokrisova et al., 2016;Morganti et al., 2013;Pai & Jacobs, 2004;Serino et al., 2014) and MCI (Antonova et al., 2009;Laczo et al., 2010), as well as in SCZ (Fajnerova et al., 2014;Ledoux et al., 2014;Salgado-Pineda et al., 2016). It has been posited that spatial memory deficits are the best indicator for poor social and occupational functioning in SCZ (Green, 1996;Green & Nuechterlein, 1999), pointing to the relevance of spatial memory tasks to socio-cognitive symptoms. ...
Central nervous system diseases are not currently diagnosed based on knowledge of biological mechanisms underlying their symptoms. Greater understanding may be offered through an agnostic approach to traditional disease categories, where learning more about shared biological mechanisms across conditions could potentially reclassify sub-groups of patients to allow realisation of more effective treatments. This review represents the output of the collaborative group "PRISM", tasked with considering assay choices for assessment of attention and working memory in a transdiagnostic cohort of Alzheimer's disease and schizophrenia patients exhibiting symptomatic spectra of social withdrawal. A multidimensional analysis of this nature has not been previously attempted. Nominated assays (continuous performance test III, attention network test, digit symbol substitution, N-back, complex span, spatial navigation in a virtual environment) reflected a necessary compromise between the need for broad assessment of the neuropsychological constructs in question with several pragmatic criteria: patient burden, compatibility with neurophysiologic measures, availability of preclinical homologues.
... Schizophrenia patients show impairments in many of these psychological processes [32][33][34][35] . Furthermore, atypical antipsychotics increase neurogenesis 36 and a number of functionally diverse schizophrenia risk genes, including DISC1 37 , SREB2/GPR85 38 , CACNA1C 39,40 DGCR8 41 , and miR137 42 , modify adult hippocampal neurogenesis in rodent models. ...
Genetic and epidemiological evidence implicate the immune system in the pathogenesis of schizophrenia but mechanistic insights are lacking. Here we show that haploinsufficiency of Cyfip1 a candidate risk gene for schizophrenia in the pathogenic 15q11.2(BP1-BP2) deletion impacts on microglia the resident immune cells of the central nervous system to cause abnormal neurogenesis in the postnatal hippocampus. We use mouse models to first demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult born hippocampal neurons without altering proliferation. We next show that the increased numbers of new born neurons are due to reduced apoptosis of immature neurons. We then demonstrate that apoptosis of immature neurons is controlled by secreted factors from microglia. Finally we show that haploinsufficiency of Cyfip1 leads to a cell autonomous failure of microglia induced neuronal apoptosis, resulting in sparing of immature neurons that would normally have been culled at this developmental check-point, with implications for maladaptive function. Our findings provide a novel mechanism linking a psychiatric risk gene with microglial dysfunction in the hippocampus, a brain area with strong evidence for involvement in psychopathology.
... Over the last few decades, the use of VR in psychotic disorders, such as schizophrenia, has been a promising candidate, for example, for a clearer understanding of symptoms, for training of instrumental and social skills, and for the treatment of the disease, as an adjuvant technique [8,9]. With reference to the stigma, VR has been shown to be useful for diminishing negative stereotypes [10] and as a supporting device to increase empathy and positive impressions towards schizophrenic people [11] amongst other applications [12][13][14][15][16][17][18][19][20][21][22][23][24]. ...
Schizophrenia is a chronic mental disease that usually manifests psychotic symptoms and affects an individual’s functionality. The stigma related to this disease is a serious obstacle for an adequate approach to its treatment. Stigma can, for example, delay the start of treatment, and it creates difficulties in interpersonal and professional relationships. This work proposes a new tool based on augmented reality to reduce the stigma related to schizophrenia. The tool is capable of simulating the psychotic symptoms typical of schizophrenia and simulates sense perception changes in order to create an immersive experience capable of generating pathological experiences of a patient with schizophrenia. The integration into the proposed environment occurs through immersion glasses and an embedded camera. Audio and visual effects can also be applied in real time. To validate the proposed environment, medical students experienced the virtual environment and then answered three questionnaires to assess (i) stigmas related to schizophrenia, (ii) the efficiency and effectiveness of the tool, and, finally (iii) stigma after simulation. The analysis of the questionnaires showed that the proposed model is a robust tool and quite realistic and, thus, very promising in reducing stigma associated with schizophrenia by instilling in the observer a greater comprehension of any person during an schizophrenic outbreak, whether a patient or a family member.
... The experimental paradigm used has been described in detail by Salgado-Pineda et al (2016). Briefly, subjects learn to navigate through a virtual city centre, which they view through virtual reality goggles using a joystick to move forwards and change direction (see Figure 1a for a bird's eye view). ...
Functional imaging studies have implicated the hippocampus and parahippocampal gyrus in cue-guided spatial navigation, but also many other regions. Furthermore, little is known about de-activations that take place during performance of navigation tasks, something that is of interest given that the hippocampus is a component of the default mode network, which de-activates during attention-demanding tasks. In this study 22 healthy subjects underwent whole-brain functional Magnetic Resonance Imaging (fMRI) while they navigated towards a previously learnt goal in a virtual reality environment. At a threshold of p<0.05 corrected, the subjects showed a pattern of widespread cortical activations, including the parahippocampal and retrosplenial cortex and also parts of the frontal, temporal and occipital cortex. Hippocampal activation, however, was restricted to the posterior portion of the structure bilaterally. De-activations were seen in the medial frontal cortex and other regions of the default mode network, but not in the posterior cingulate cortex/precuneus. The findings support the involvement of the hippocampus in cue-guided navigation, but suggest that its posterior regions are particularly important. Cue-guided spatial navigation is associated with de-activation in some but not all parts of the default mode network.
... Most works analysed declare that tasks included were adapted to final users, taking into account primarily their cognitive capabilities, but providing no special attention to technological issues. For example, task difficulty is typically adapted by adjusting the number of stimuli or their presentation speed (Delgado et al., 2016;Tong & Chignell, 2014), or the type of navigation that the user can perform (Salgado-Pineda et al., 2016;Armstrong et al., 2013;Plancher et al., 2012). With respect to the interaction device utilized, the TV set is only marginally present when compared to other devices like the personal computer or the mobile phone. ...
Introduction:
The computing capabilities of state-of-the-art television sets and media centres may facilitate the introduction of computer-assisted evaluation at home. This approach would help to overcome the drawbacks of traditional pen-and-paper evaluations administered in clinical facilities, as they could be performed in a more comfortable environment, the subject's home, and they would be more flexible for designing complex environments for the evaluation of neuropsychological constructs that are difficult to assess through traditional testing. The objective of this work was to obtain some initial evidence about the technical acceptance by senior adults of serious games played at home on the TV set and therefore about the convenience of further investigating such an approach to cognitive assesment.
Materials and methods:
We developed a collection of games to be deployed on a TV environment. These games were tried by a group of senior adults at their homes. The Technology Acceptance Model (TAM) was used to validate this approach. Surveys were performed to study the perceived usefulness and perceived ease of use of such technical setting as an instrument for their cognitive evaluation; that is, its technical acceptance. Subjective information collected from participants was correlated with actual interaction data captured. An additional survey was performed 36 months after pilot testing to have an indication about the long-term perceptions about usefulness and ease of use.
Results:
More than 90% of participating subjects perceived cognitive games on TV as useful or very useful. The majority of participants selected the TV set as their preferred option to interact with serious games at home, when compared to other devices such as smartphones, tablets or PCs. This result correlates with the number of participants perceiving them as easily usable or very easy to use, and also with automatically captured interaction data. Three out of four seniors expressed their interest in keeping the system at home after the pilot. Besides, these perceptions are fairly stable in time as shown by the survey performed 36 months after pilot testing.
Limitations:
Although participating users are a representative sample of the Galician population, which in turn is comparable to the population of most rural areas in Europe, a larger and more diverse user sample would be needed to obtain significant results for a wider population profile.
Conclusion:
The study confirmed the technical acceptance, that is, the perceived usefulness and perceived ease of use, of the TV-based home technical setting introduced as a means of cognitive evaluation. This study provides initial evidence on the viability of a TV-based serious games approach for cognitive longitudinal screening at home with little intervention of clinical professionals, thus contributing to the early detection of cognitive impairments in the senior population.
This chapter will provide a review of research into human cognition through the lens of VR-based paradigms for studying memory. Emphasis is placed on why VR increases the ecological validity of memory research and the implications of such enhancements.KeywordsVirtual realityCognitionMemoryCognitive enhancementMemory enhancementCognitive assessmentsMemory assessmentsCognitive rehabilitationMemory rehabilitationEmbodied cognitionEmbodied memoryExtended cognitionExtended memoryEnvironmental enrichment
The hippocampal formation has been implicated in the pathophysiology of schizophrenia, with patients showing impairments in spatial and relational cognition, structural changes in entorhinal cortex, and reduced theta coherence with medial prefrontal cortex. Both the entorhinal cortex and medial prefrontal cortex exhibit a six-fold (or ‘hexadirectional’) modulation of neural activity during virtual navigation that is indicative of grid cell populations and associated with accurate spatial navigation.
Here, we examined whether these grid-like patterns are disrupted in schizophrenia. We asked 17 participants with diagnoses of schizophrenia and 23 controls (matched for age, sex and IQ) to perform a virtual reality spatial navigation task during magnetoencephalography.
The control group showed stronger 4-10 Hz theta power during movement onset, as well as hexadirectional modulation of theta band oscillatory activity in the right entorhinal cortex whose directional stability across trials correlated with navigational accuracy. This hexadirectional modulation was absent in patients, with a significant difference between groups.
These results suggest that impairments in spatial and relational cognition associated with schizophrenia may arise from disrupted grid firing patterns in entorhinal cortex.
Spatial memory and reward processing are known to be disrupted in schizophrenia. Since the lateral septum (LS) may play an important role in the integration of location and reward, we examined the effect of maternal immune activation (MIA), a known schizophrenia risk factor, on spatial representation in the rat LS. In support of a previous study, we found that spatial location is represented as a phase code in the rostral LS of adult male rats, so that LS cell spiking shifts systematically against the phase of the hippocampal, theta-frequency, local field potential (LFP) as an animal moves along a track towards a reward (phase precession). Whereas shallow precession slopes were observed in control (CTL) group cells, they were steeper in the MIA animals, such that firing frequently precessed across several theta cycles as the animal moved along the length of the apparatus, with subsequent ambiguity in the phase representation of location. Furthermore, an analysis of the phase trajectories of the CTL group cells revealed that the population tended to converge towards a common firing phase as the animal approached the reward location. This suggested that phase coding in these cells might signal both reward location and the distance to reward. By comparison the degree of phase convergence in the MIA-group cells was weak, and the region of peak convergence was distal to the reward location. These findings suggest that a schizophrenia risk factor disrupts the phase-based encoding of location-reward relationships in the LS, potentially smearing reward representations across space.
Different strategies may be spontaneously adopted to solve most navigation tasks. These strategies are associated with dissociable brain systems. Here, we use brain-imaging and cognitive tasks to test the hypothesis that individuals living with Schizophrenia Spectrum Disorders (SSD) have selective impairment using a hippocampal-dependent spatial navigation strategy. Brain activation and memory performance were examined using functional magnetic resonance imaging (fMRI) during the 4-on-8 virtual maze (4/8VM) task, a human analog of the rodent radial-arm maze that is amenable to both response-based (egocentric or landmark-based) and spatial (allocentric, cognitive mapping) strategies to remember and navigate to target objects. SSD (schizophrenia and schizoaffective disorder) participants who adopted a spatial strategy performed more poorly on the 4/8VM task and had less hippocampal activation than healthy comparison participants using either strategy as well as SSD participants using a response strategy. This study highlights the importance of strategy use in relation to spatial cognitive functioning in SSD. Consistent with a selective-hippocampal dependent deficit in SSD, these results support the further development of protocols to train impaired hippocampal-dependent abilities or harness non-hippocampal dependent intact abilities.
In the past 20 years, many studies in the cognitive neurosciences have analyzed human ability to navigate in recently learned and familiar environments by investigating the cognitive processes involved in successful navigation. In this study, we reviewed the main experimental paradigms and made a cognitive-oriented meta-analysis of fMRI studies of human navigation to underline the importance of the experimental designs and cognitive tasks used to assess navigational skills. We performed a general activation likelihood estimation (ALE) meta-analysis of 66 fMRI experiments to identify the neural substrates underpinning general aspects of human navigation. Four individual ALE analyses were performed to identify the neural substrates of different experimental paradigms (i.e., familiar vs. recently learned environments) and different navigational strategies (allocentric vs. egocentric). Results of the general ALE analysis highlighted a wide network of areas with clusters in the occipital, parietal, frontal and temporal lobes, especially in the parahippocampal cortex. Familiar environments seem to be processed by an extended temporal-frontal network, whereas recently learned environments require activation in the parahippocampal cortex and the parietal and occipital lobes. Allocentric strategy is subtended by the same areas as egocentric strategy, but the latter elicits greater activation in the right precuneus, middle occipital lobe and angular gyrus. Our results suggest that different neural correlates are involved in recalling a well-learned or recently acquired environment and that different networks of areas subtend egocentric and allocentric strategies.
Electronic supplementary material
The online version of this article (doi:10.1007/s11065-014-9247-8) contains supplementary material, which is available to authorized users.
Psychotic symptoms in schizophrenia are related to disturbed self-recognition and to disturbed experience of agency. Possibly, these impairments contribute to first-person large-scale egocentric learning deficits. Sixteen inpatients with schizophrenia and 16 matched healthy comparison subjects underwent functional magnetic resonance imaging (fMRI) while finding their way in a virtual maze. The virtual maze presented a first-person view, lacked any topographical landmarks and afforded egocentric navigation strategies. The participants with schizophrenia showed impaired performance in the virtual maze when compared with controls, and showed a similar but weaker pattern of activity changes during egocentric learning when compared with controls. Especially the activity of task-relevant brain regions (precuneus and posterior cingulate and retrosplenial cortex) differed from that of controls across all trials of the task. Activity increase within the right-sided precuneus was related to worse virtual maze performance and to stronger positive symptoms in participants with schizophrenia. We suggest that psychotic symptoms in schizophrenia are related to aberrant neural activity within the precuneus. Possibly, first-person large-scale egocentric navigation and learning designs may be a feasible tool for the assessment and treatment of cognitive deficits related to self-recognition in patients with schizophrenia.
Although structural brain alterations in schizophrenia have been demonstrated extensively, their quantitative distribution has not been studied over the last 14 years despite advances in neuroimaging. Moreover, a volumetric meta-analysis has not been conducted in antipsychotic-naive patients. Therefore, meta-analysis on cross-sectional volumetric brain alterations in both medicated and antipsychotic-naive patients was conducted. Three hundred seventeen studies published from September 1, 1998 to January 1, 2012 comprising over 9000 patients were selected for meta-analysis, including 33 studies in antipsychotic-naive patients. In addition to effect sizes, potential modifying factors such as duration of illness, sex composition, current antipsychotic dose, and intelligence quotient matching status of participants were extracted where available. In the sample of medicated schizophrenia patients (n = 8327), intracranial and total brain volume was significantly decreased by 2.0% (effect size d = -0.17) and 2.6% (d = -0.30), respectively. Largest effect sizes were observed for gray matter structures, with effect sizes ranging from -0.22 to -0.58. In the sample of antipsychotic-naive patients (n = 771), volume reductions in caudate nucleus (d = -0.38) and thalamus (d = -0.68) were more pronounced than in medicated patients. White matter volume was decreased to a similar extent in both groups, while gray matter loss was less extensive in antipsychotic-naive patients. Gray matter reduction was associated with longer duration of illness and higher dose of antipsychotic medication at time of scanning. Therefore, brain loss in schizophrenia is related to a combination of (early) neurodevelopmental processes-reflected in intracranial volume reduction-as well as illness progression.
Dysfunction of the dorsolateral prefrontal cortex (DLPFC) and parahippocampal region along with poor working memory are common neurophysiological and behavioral features associated with schizophrenia and normal aging. It is, however, unknown whether the associated patterns of neural activation differ between these two groups when their cognitive performance is closely matched in a pairwise manner. The authors sought to pinpoint common and differential pathophysiological features that accompany comparable working memory impairments in schizophrenia and healthy aging.
Fifty-three subjects were scanned with oxygen-15 water positron emission tomography regional cerebral blood flow measurements during working memory. Seventeen medication-free patients with schizophrenia were individually matched for working memory performance with 17 healthy aging subjects. Brain activation of the two index groups were compared with each other and with 19 young healthy individuals.
Patients with schizophrenia showed right DLPFC hypoactivation, both when compared with age-matched control subjects and after direct comparison with working memory performance-matched elderly subjects. Moreover, both groups with working memory deficits shared an inability to suppress parahippocampal and anterior medial prefrontal cortex activation.
These results provide new insights into the mechanisms by which impaired working memory performance can arise by showing that both common (parahippocampal/anterior medial PFC) and differential (DLPFC) pathophysiological features accompany similar cognitive impairments. The aging data also demonstrate that poor performance is not necessarily accompanied by the DLPFC hypofunction that was seen in schizophrenia. Finally, these results more closely link the DLPFC functional abnormalities in schizophrenia to the pathophysiology of the disorder rather than to poor performance per se.
It is not known whether first-episode psychosis is characterized by the same prefrontal cortex functional imaging abnormalities as chronic schizophrenia.
Thirty patients with a first episode of non-affective functional psychosis and 28 healthy controls underwent functional magnetic resonance imaging (fMRI) during performance of the n-back working memory task. Voxel-based analyses of brain activations and deactivations were carried out and compared between groups. The connectivity of regions of significant difference between the patients and controls was also examined.
The first-episode patients did not show significant prefrontal hypo- or hyperactivation compared to controls. However, they showed failure of deactivation in the medial frontal cortex. This area showed high levels of connectivity with the posterior cingulate gyrus/precuneus and parts of the parietal cortex bilaterally. Failure of deactivation was significantly greater in first-episode patients who had or went on to acquire a DSM-IV diagnosis of schizophrenia than in those who did not, and in those who met RDC criteria for schizophrenia compared to those who did not.
First-episode psychosis is not characterized by hypo- or hyperfrontality but instead by a failure of deactivation in the medial frontal cortex. The location and connectivity of this area suggest that it is part of the default mode network. The failure of deactivation seems to be particularly marked in first-episode patients who have, or progress to, schizophrenia.
Cognitive impairment is an established feature of schizophrenia. However, little is known about its relationship to the structural and functional brain abnormalities that characterise the disorder. Aims To identify structural and/or functional brain abnormalities associated with schizophrenic cognitive impairment.
We carried out structural magnetic resonance imaging (MRI) and voxel-based morphometry in 26 participants who were cognitively impaired and 23 who were cognitively preserved, all with schizophrenia, plus 39 matched controls. Nineteen of those who were cognitively impaired and 18 of those who were cognitively preserved plus 34 controls also underwent functional MRI during performance of a working memory task.
No differences were found between the participants who were cognitively intact and those who were cognitively impaired in lateral ventricular volume or whole brain volume. Voxel-based morphometry also failed to reveal clusters of significant difference in grey and white matter volume between these two groups. However, during performance of the n-back task, the participants who were cognitively impaired showed hypoactivation compared with those who were cognitively intact in the dorsolateral prefrontal cortex among other brain regions.
Cognitive impairment in schizophrenia is not a function of the structural brain abnormality that accompanies the disorder but has correlates in altered brain function.
The neural basis of navigation by humans was investigated with functional neuroimaging of brain activity during navigation
in a familiar, yet complex virtual reality town. Activation of the right hippocampus was strongly associated with knowing
accurately where places were located and navigating accurately between them. Getting to those places quickly was strongly
associated with activation of the right caudate nucleus. These two right-side brain structures function in the context of
associated activity in right inferior parietal and bilateral medial parietal regions that support egocentric movement through
the virtual town, and activity in other left-side regions (hippocampus, frontal cortex) probably involved in nonspatial aspects
of navigation. These findings outline a network of brain areas that support navigation in humans and link the functions of
these regions to physiological observations in other mammals.
The hippocampal formation is one of the most extensively studied regions of the brain, with well-described anatomy and basic physiology; moreover, aspects of human memory mediated by the hippocampus are well characterized. In schizophrenia, alterations in hippocampal anatomy, perfusion, and activation are consistently reported; impairments in declarative memory function, especially in the flexible use of event memories (e.g., in the service of memory-based inference), are common. Postmortem molecular changes suggest a selective reduction in glutamate transmission in the dentate gyrus and in its efferent fibers, the mossy fiber pathway. A reduction in dentate gyrus glutamatergic output and in its information processing functions could generate two co-occurring outcomes in the hippocampus: 1) a change in homeostatic plasticity processes in cornu ammonis 3 (CA3), accompanied by increased activity due to reduced afferent stimulation from the dentate gyrus onto CA3 neurons, a process that could increase the pattern completion functions of CA3, and 2) the loss of mnemonic functions specific to the dentate gyrus, namely pattern separation, a change that could increase the prevalence of illusory pattern completion and reduce discrimination between present and past experiences in memory. The resulting increase in "runaway" CA3-mediated pattern completion could result in cognitive "mistakes," generating psychotic associations and resulting in memories with psychotic content. Tests of this model could result in novel approaches to the treatment of psychosis and declarative memory alterations and in novel animal preparations for basic schizophrenia research.
The hippocampus is crucial for both spatial navigation and episodic memory, suggesting that it provides a common function to both. Here we adapt a spatial paradigm, developed for rodents, for use with functional MRI in humans to show that activation of the right hippocampus predicts the use of an allocentric spatial representation, and activation of the left hippocampus predicts the use of a sequential egocentric representation. Both representations can be identified in hippocampal activity before their effect on behavior at subsequent choice-points. Our results suggest that, rather than providing a single common function, the two hippocampi provide complementary representations for navigation, concerning places on the right and temporal sequences on the left, both of which likely contribute to different aspects of episodic memory.
The past decade has seen a transformation in research on the retrosplenial cortex (RSC). This cortical area has emerged as a key member of a core network of brain regions that underpins a range of cognitive functions, including episodic memory, navigation, imagination and planning for the future. It is now also evident that the RSC is consistently compromised in the most common neurological disorders that impair memory. Here we review advances on multiple fronts, most notably in neuroanatomy, animal studies and neuroimaging, that have highlighted the importance of the RSC for cognition, and consider why specifying its precise functions remains problematic.
Prefrontal cortical dysfunction is frequently reported in schizophrenia. It remains unclear whether this represents the coincidence of several prefrontal region- and process-specific impairments or a more unitary dysfunction in a superordinate cognitive control network. Whether these impairments are properly considered reflective of hypofrontality vs hyperfrontality remains unresolved.
To test whether common nodes of the cognitive control network exhibit altered activity across functional neuroimaging studies of executive cognition in schizophrenia and to evaluate the direction of these effects.
PubMed database.
Forty-one English-language, peer-reviewed articles published prior to February 2007 were included. All reports used functional neuroimaging during executive function performance by adult patients with schizophrenia and reported whole-brain analyses in standard stereotactic space. Tasks primarily included the delayed match-to-sample, N-back, AX-CPT, and Stroop tasks.
Activation likelihood estimation modeling reported activation maxima as the center of a 3-dimensional gaussian function in the meta-analysis, with statistical thresholding and correction for multiple comparisons.
In within-group analyses, healthy controls and patients activated a similarly distributed cortical-subcortical network, prominently including the dorsolateral prefrontal cortex (PFC), ventrolateral PFC, anterior cingulate cortex (ACC), and thalamus. In between-group analyses, patients showed reduced activation in the left dorsolateral PFC, rostral/dorsal ACC, left thalamus (with significant co-occurrence of these areas), and inferior/posterior cortical areas. Increased activation was observed in several midline cortical areas. Activation within groups varied modestly by task.
Healthy adults and schizophrenic patients activate a qualitatively similar neural network during executive task performance, consistent with the engagement of a general-purpose cognitive control network, with critical nodes in the dorsolateral PFC and ACC. Nevertheless, patients with schizophrenia show altered activity with deficits in the dorsolateral PFC, ACC, and mediodorsal nucleus of the thalamus. Increases in activity are evident in other PFC areas, which could be compensatory in nature.
Application of a neuropsychological perspective to the study of schizophrenia has established a number of important facts about this disorder. Some of the key findings from the existing literature are that, while neurocognitive impairment is present in most, if not all, persons with schizophrenia, there is both substantial interpatient heterogeneity and remarkable within-patient stability of cognitive function over the long-term course of the illness. Such findings have contributed to the firm establishment of neurobiologic models of schizophrenia, and thereby help to reduce the social stigma that was sometimes associated with purely psychogenic models popular during parts of the 20th century. Neuropsychological studies in recent decades have established the primacy of cognitive functions over psychopathologic symptoms as determinants of functional capacity and independence in everyday functioning. Although the cognitive benefits of both conventional and even second generation antipsychotic medications appear marginal at best, recognition of the primacy of cognitive deficits as determinants of functional disability in schizophrenia has catalyzed recent efforts to develop targeted treatments for the cognitive deficits of this disorder. Despite these accomplishments, however, some issues remain to be resolved. Efforts to firmly establish the specific neurocognitive/neuropathologic systems responsible for schizophrenia remain elusive, as do efforts to definitively demonstrate the specific cognitive deficits underlying specific forms of functional impairment. Further progress may be fostered by recent initiatives to integrate neuropsychological studies with experimental neuroscience, perhaps leading to measures of deficits in cognitive processes more clearly associated with specific, identifiable brain systems.
Episodic memory impairments represent a core deficit in schizophrenia that severely limits patients' functional outcome. This quantitative meta-analysis of functional imaging studies of episodic encoding and retrieval tests the prediction that these deficits are most consistently associated with dysfunction in the prefrontal cortex.
Activation likelihood estimation (ALE) was used to perform a quantitative meta-analysis of functional imaging studies that contrasted patients with schizophrenia and healthy volunteers during episodic encoding and retrieval. From a pool of 36 potential studies, 18 whole-brain studies in standard space that included a healthy comparison sample and low-level baseline contrast were selected.
As predicted, patients showed less prefrontal activation than comparison subjects in the frontal pole, dorsolateral and ventrolateral prefrontal cortex during encoding, and the dorsolateral prefrontal cortex and ventrolateral prefrontal cortex during retrieval. The ventrolateral prefrontal cortex encoding deficits were not present in studies that provided patients with encoding strategies, but dorsolateral prefrontal cortex deficits remained and were not secondary to group performance differences. The only medial temporal lobe finding was relatively greater patient versus comparison subject activation in the parahippocampal gyrus during encoding and retrieval.
The finding of prominent prefrontal dysfunction suggests that cognitive control deficits strongly contribute to episodic memory impairment in schizophrenia. Memory rehabilitation approaches developed for patients with frontal lobe lesions and pharmacotherapy approaches designed to improve prefrontal cortex function may therefore hold special promise for remediating memory deficits in patients with schizophrenia.
The hippocampus has been proposed as the site of neural representation of large-scale environmental space, based upon the
identification of place cells (neurons with receptive fields for current position in the environment) within the rat hippocampus
and the demonstration that hippocampal lesions impair place learning in therat. The inability to identify place cells within
the monkey hippocampus and the observation that unilateral hippocampal lesions do not selectively impair topographic behavior
in humans suggest that alternate regions may subserve this function in man. To examine the contribution of the hippocampus
and adjacent medial-temporal lobe structures to topographic learning in the human, a ‘virtual’ maze was used as a task environment
during functional magnetic resonance imaging studies. During the learning and recall of topographic information, medial-temporal
activity was confined to the para- hippocampal gyri. This activity accords well with the lesion site known to produce topographical
disorientation in humans. Activity was also observed in cortical areas known to project to the parahippocampus and previously
proposed to contribute to a network subserving spatially guided behavior.
Visuospatial navigation in animals and human subjects is generally studied using maze exploration. We used functional MRI to observe brain activation in male and female subjects as they searched for the way out of a complex, three-dimensional, virtual-reality maze. Navigation activated the medial occipital gyri, lateral and medial parietal regions, posterior cingulate and parahippocampal gyri as well as the right hippocampus proper. Gender-specific group analysis revealed distinct activation of the left hippocampus in males, whereas females consistently recruited right parietal and right prefrontal cortex. Thus we demonstrate a neural substrate of well established human gender differences in spatial-cognition performance.
A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
Hippocampal activation was investigated, comparing allocentric and egocentric spatial memory. Healthy participants were immersed in a virtual reality circular arena, with pattern-rendered walls. In a viewpoint-independent task, they moved toward a pole, which was then removed. They were relocated to another position and had to move to the prior location of the pole. For viewpoint-dependent memory, the participants were not moved to a new starting point, but the patterns were rotated to prevent them from indicating the final position. Hippocampal and parahippocampal activation were found in the viewpoint-independent memory encoding phase. Viewpoint-dependent memory did not result in such activation. These results suggest differential activation of the hippocampal formation during allocentric encoding, in partial support of the spatial mapping hypothesis as applied to humans.
Numerous studies have examined the neural correlates of episodic memory deficits in schizophrenia, yielding both consistencies and discrepancies in the reported patterns of results.
To identify in schizophrenia the brain regions in which activity is consistently abnormal across imaging studies of memory.
Data from 18 studies meeting the inclusion criteria were combined using a recently developed quantitative meta-analytic approach.
Regions of consistent differential activation between groups were observed in the left inferior prefrontal cortex, medial temporal cortex bilaterally, left cerebellum, and in other prefrontal and temporal lobe regions. Subsequent analyses explored memory encoding and retrieval separately and identified between-group differences in specific prefrontal and medial temporal lobe regions.
Beneath the apparent heterogeneity of published findings on schizophrenia and memory, a consistent and robust pattern of group differences is observed as a function of memory processes.
Memory deficits are common in schizophrenia. Recent studies have demonstrated that relational memory is particularly impaired.
To study the neural correlates of relational memory in schizophrenia using functional magnetic resonance imaging.
Cross-sectional case-control study.
Academic medical center. Subjects Twenty patients with schizophrenia and 17 control subjects.
Behavioral performance and brain activity were assessed during the discrimination of previously seen and novel pairs of visual stimuli, which varied in the degree of relational memory load. We performed whole-brain and region-of-interest (hippocampus) analyses.
Schizophrenic subjects displayed normal activation of the presupplementary motor area and ventral prefrontal cortex, but significantly decreased recruitment of the right parietal cortex and anterior cingulate cortex when discriminating novel pairs derived from a sequence of stimuli. Discrimination accuracy was decreased in schizophrenia only when the flexible representation of a sequence was required. This selective deficit was associated with decreased activation of the right parietal cortex and left hippocampus.
Schizophrenia is characterized by a specific deficit of relational memory, which is associated with impaired function of the parietal cortex and hippocampus. Abnormal relational memory may be at the core of 2 prominent features of schizophrenia, ie, cognitive deficits and psychosis.
Sleep promotes the integration of recently acquired spatial memories into cerebral networks for the long term. In this study, we examined how sleep deprivation hinders this consolidation process. Using functional MRI, we mapped regional cerebral activity during place-finding navigation in a virtual town, immediately after learning and 3 days later, in subjects either allowed regular sleep (RS) or totally sleep-deprived (TSD) on the first posttraining night. At immediate and delayed retrieval, place-finding navigation elicited increased brain activity in an extended hippocampo-neocortical network in both RS and TSD subjects. Behavioral performance was equivalent between groups. However, striatal navigation-related activity increased more at delayed retrieval in RS than in TSD subjects. Furthermore, correlations between striatal response and behavioral performance, as well as functional connectivity between the striatum and the hippocampus, were modulated by posttraining sleep. These data suggest that brain activity is restructured during sleep in such a way that navigation in the virtual environment, initially related to a hippocampus-dependent spatial strategy, becomes progressively contingent in part on a response-based strategy mediated by the striatum. Both neural strategies eventually relate to equivalent performance levels, indicating that covert reorganization of brain patterns underlying navigation after sleep is not necessarily accompanied by overt changes in behavior.
• functional MRI
• hippocampus
• sleep deprivation
• memory consolidation
• striatum
Until recently, the dominant view was that schizophrenia patients have limited, if any, neuropsychological impairments, and those that are observed are only secondary to the florid symptoms of the disorder. This view has dramatically changed. This review integrates recent evidence demonstrating the severity and profile of neuropsychological impairments in schizophrenia. We present quantitative evaluation of the literature demonstrating that the most severe impairments are apparent in episodic memory and executive control processes, evident on a background of a generalized cognitive deficit. The neuropsychological impairments potentially represent genetic liability to the disorder, as similar, yet milder, impairments are evident in schizophrenia patients even before the onset of psychotic symptoms, as well as in the nonpsychotic relatives of schizophrenia patients. Corresponding cognitive neuroimaging literature on executive functions, episodic memory, and working memory in schizophrenia documenting abnormalities in frontal and medial temporal lobes is summarized, and current models integrating neuropsychological and neuroimaging data are discussed.
Schizophrenia is associated with abnormalities of hippocampal structure and function. Neuroimaging studies have shown that the hippocampus is hyperactive in schizophrenia. Here we explore GABAergic mechanisms of this hippocampal hyperactivity.
The initial evidence for GABAergic abnormalities of the hippocampus in schizophrenia came from post-mortem studies of interneuron number, protein expression, and gene expression. These studies revealed marked decreases in gene and protein expression of somatostatin-positive and parvalbumin-positive interneurons, and indicated reduced interneuron numbers. Animal studies of decreased parvalbumin and NMDA-receptor function have shown that selective abnormalities of hippocampal interneurons mimic some of the cognitive deficits and clinical features of schizophrenia.
The post-mortem and animal studies are consistent with the neuroimaging finding of increased hippocampal activity in schizophrenia, which can explain some of the psychotic symptoms and cognitive deficits. Taken together, these findings may guide the development of biomarkers and the development of new treatments for psychosis.
Importance
Declarative memory—the ability to learn, store, and retrieve information—has been consistently reported to be altered in schizophrenia, and hippocampal-parahippocampal dysfunction has been implicated in this deficit. To elucidate the possible role of genetic risk factors in such findings, it is necessary to study healthy relatives of patients with schizophrenia who carry risk-associated genes but not the confounding factors related to the disorder.Objective
To investigate whether altered brain responses, particularly in the hippocampus and parahippocampus, during the encoding phase of a simple declarative memory task are also observed in unaffected siblings who are at increased genetic risk for schizophrenia.Design, Setting, and Participants
Functional magnetic resonance imaging was used with a simple visual declarative memory paradigm to test for differences in neural activation across normal control participants, patients with schizophrenia, and their healthy siblings. This study was conducted at a research center and included a total of 308 participants (181 normal control participants, 65 healthy siblings, and 62 patients with schizophrenia); all participants were white of European ancestry.Main Outcomes and Measures
All participants completed a declarative memory task involving incidental encoding of neutral visual scenes interleaved with crosshair fixation while undergoing functional magnetic resonance imaging. Differences in hippocampus and parahippocampus activation and coupling across groups and correlations with accuracy were analyzed. Analyses were repeated in pairwise-matched samples.Results
Both patients with schizophrenia and their healthy siblings showed reduced parahippocampal activation (bilaterally) and hippocampal-parietal (BA 40) coupling during the encoding of novel stimuli when compared with normal control participants. There was a significant positive correlation between parahippocampal activation during encoding and the visual-memory score.Conclusions and Relevance
These results suggest that altered hippocampal-parahippocampal function during encoding is an intermediate biologic phenotype related to increased genetic risk for schizophrenia. Therefore, measuring hippocampal-parahippocampal function with neuroimaging represents a potentially useful approach to understanding genetic mechanisms that confer risk for schizophrenia.
The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibil- ity, sensitivity and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions which could not previously be answered and, as such, has become an important research area in its own right. In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data . The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL).
Intact episodic memory requires the ability to make associations between the contextual features of an event, referred to as contextual binding. Binding processes combine different contextual elements into a complete memory representation. It has been proposed that binding errors during the encoding process are responsible for the episodic memory impairments reported in schizophrenia. Since the hippocampus is critical for contextual binding and episodic memory, it was hypothesized that patients with schizophrenia would show a deficit in information processing in the hippocampus, measured with functional magnetic resonance imaging (fMRI). In the current experiment, 21 patients with schizophrenia and 22 healthy control participants were scanned while being tested on navigating in a virtual town (i.e. find the grocery store from the school), a task that was shown to be critically dependent on the hippocampus. Between-group comparisons revealed significantly less activation among patients relative to controls in the left middle frontal gyrus, and right and left hippocampi. We propose that the context and the content are not appropriately linked, therefore affecting the formation of a cognitive map representation in the patient group and eliciting a contextual binding deficit.
This paper presents results and experiences coming from 10 years of development and use of XVR, a flexible, general-purpose framework for virtual reality (VR) development. The resulting architecture, that comes under the form of a self-sufficient integrated development environment (IDE) organized around a dedicated scripting language and a virtual machine, is able to accommodate a wide range of applications needs, ranging from simple Web3D applications to motion-based simulators or complex cluster-based immersive visualization systems. Within the framework a common, archetypical structure is used for any application, showing how inhomogeneous needs and technologies can be effectively covered by using a single, rather simple, system organization. We also show how the framework flexibility allows for innovative development techniques such as multiple frameworks coexisting within a single, tightly integrated, VR application.
For decades, the predominant hypothesis of schizophrenia centered on dysfunctions of the dopamine system. However, recent evidence now suggests that the dopamine system may be "normal" in its configuration, but instead is regulated abnormally by modulatory processes. Convergent studies in animals and in humans have now focused on the hippocampus as a central component in the generation of psychosis and possibly other symptom states in schizophrenia. Thus, activity in the ventral hippocampus has been shown to regulate dopamine neuron responsivity by controlling the number of dopamine neurons that can be phasically activated by stimuli. In this way, this structure determines the gain of the dopamine signal in response to stimuli. However, in schizophrenia, the hippocampus appears to be hyper-active, possibly due to attenuation of function of inhibitory interneurons. As a result, the dopamine system is driven into an overly responsive state. Current medications have focused on blockade of overstimulated dopamine receptors; however, this now appears to be several synapses downstream from the pathological antecedent. Therapeutic approaches that focus on normalizing hippocampal function may prove to be more effective treatment avenues for the schizophrenia patient.
The activity of brain regions of the so-called default mode network (DMN) attenuates during the performance of goal-directed tasks. These activity decreases (named task-induced deactivations; TID) are though to reflect the reallocation of cognitive resources from the DMN to areas implicated in the execution of the task. Recently, DMN activity suppression has been studied in schizophrenia patients. Although these works showed that TID are altered in schizophrenia, they also revealed inconsistent findings. We hypothesized that reallocation of resources is altered in schizophrenia patients and is context or task specific. We investigated TID using functional MRI in 26 schizophrenic patients and 13 control subjects while performing two different goal-directed tasks (the Hayling Sentence Completion Test and the N-Back task). Both whole brain and region of interest conjunction analyses were conducted to investigate brain areas commonly deactivated in the two tasks (task unspecific deactivations). Task-unspecific deactivations were not observed in the schizophrenia group, although these were strongly significant in the control group. Differences between patient and control participants were observed in different regions of the DMN depending whether the subjects performed the Hayling or the N-back task. These results suggest that reallocation of cognitive resources is altered in our patient sample. Moreover, TID were task-unspecific indicating that resources reallocation is context dependent in schizophrenia. DMN activity attenuates differently in schizophrenia patients depending on the cognitive processes involved in the task.
There is increasing evidence of default mode network (DMN) dysfunction in schizophrenia. It has also been suggested that brain structural changes are maximal in a medial frontal area which overlaps with the anterior midline node of this network.
Brain deactivations were examined in 14 schizophrenic patients and 14 controls during performance of two tasks requiring identification or labelling of facial emotions. Grey matter and white matter volumes were compared using voxel-based morphometry.
Relative to the controls, the schizophrenic patients showed failure to deactivate in the anterior and posterior midline nodes of the default mode network, as well as other areas considered to be part of the network. Grey matter volume reductions in the patients were found in medial cortical regions which overlapped with the same parts of the network. The functional and structural changes showed significant correlations in a number of medial cortical areas.
Failure of deactivation in the default mode network is seen in schizophrenic patients when they perform facial emotion tasks. This failure is more extensive than that seen during performance of working memory tasks. The study also supports recent findings of brain structural changes in schizophrenia in the territory of the default mode network.
A functional segregation along the posterior-anterior axis of the medial temporal lobe (MTL) has been suggested. In brief, it is thought that the posterior hippocampus represents environmental detail and/or encodes space, whereas the anterior part represents the environment more as a whole and/or subserves behavior. Different phases of navigation should thus recruit different structures within the MTL. Based on animal studies and neuroimaging data from humans, the initial phase of navigation, i.e., self-localization, target localization and path planning, should depend on the anterior MTL independent of upcoming navigational demands, whereas posterior MTL should be active throughout navigation. We tested this prediction using fMRI with navigation in a learned large-scale virtual office landscape with numerous complex landmarks under different navigational conditions.
Although temporo-parietal cortices mediate spatial navigation in animals and humans, the neural correlates of reward-based spatial learning are less well known. Twenty-five healthy adults performed a virtual reality fMRI task that required learning to use extra-maze cues to navigate an 8-arm radial maze and find hidden rewards. Searching the maze in the spatial learning condition compared to the control conditions was associated with activation of temporo-parietal regions, albeit not including the hippocampus. The receipt of rewards was associated with activation of the hippocampus in a control condition when using the extra-maze cues for navigation was rendered impossible by randomizing the spatial location of cues. Our novel experimental design allowed us to assess the differential contributions of the hippocampus and other temporo-parietal areas to searching and reward processing during reward-based spatial learning. This translational research will permit parallel studies in animals and humans to establish the functional similarity of learning systems across species; cellular and molecular studies in animals may then inform the effects of manipulations on these systems in humans, and fMRI studies in humans may inform the interpretation and relevance of findings in animals.
Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task-related networks permits the quantification of this network both during task (task-induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed-based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed-based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia.
We examined the status of the neural network mediating the default mode of brain function, which typically exhibits greater activation during rest than during task, in patients in the early phase of schizophrenia and in young first-degree relatives of persons with schizophrenia. During functional MRI, patients, relatives, and controls alternated between rest and performance of working memory (WM) tasks. As expected, controls exhibited task-related suppression of activation in the default network, including medial prefrontal cortex (MPFC) and posterior cingulate cortex/precuneus. Patients and relatives exhibited significantly reduced task-related suppression in MPFC, and these reductions remained after controlling for performance. Increased task-related MPFC suppression correlated with better WM performance in patients and relatives and with less psychopathology in all 3 groups. For WM task performance, patients and relatives had greater activation in right dorsolateral prefrontal cortex (DLPFC) than controls. During rest and task, patients and relatives exhibited abnormally high functional connectivity within the default network. The magnitudes of default network connectivity during rest and task correlated with psychopathology in the patients. Further, during both rest and task, patients exhibited reduced anticorrelations between MPFC and DLPFC, a region that was hyperactivated by patients and relatives during WM performance. Among patients, the magnitude of MPFC task suppression negatively correlated with default connectivity, suggesting an association between the hyperactivation and hyperconnectivity in schizophrenia. Hyperactivation (reduced task-related suppression) of default regions and hyperconnectivity of the default network may contribute to disturbances of thought in schizophrenia and risk for the illness.
Spatial navigation is a core cognitive ability in humans and animals. Neuroimaging studies have identified two functionally defined brain regions that activate during navigational tasks and also during passive viewing of navigationally relevant stimuli such as environmental scenes: the parahippocampal place area (PPA) and the retrosplenial complex (RSC). Recent findings indicate that the PPA and RSC have distinct and complementary roles in spatial navigation, with the PPA more concerned with representation of the local visual scene and RSC more concerned with situating the scene within the broader spatial environment. These findings are a first step towards understanding the separate components of the cortical network that mediates spatial navigation in humans.
The Word Accentuation Test assesses the accentuation of 30 infrequent Spanish words written without the accentuation mark and is an easy-to-use tool for estimating premorbid intelligence of Spanish-speaking people. Its intraobserver (0.97) and interobserver (0.93) reliabilities and its correlation with the Wechsler Adult Intelligence Scale (.837) and Raven's Progressive Matrices (.655) are high, offering a good prediction of general intelligence. It is resistant to mental deterioration; 20 demented and 40 controls matched by sex, age, and education obtained similar scores. The discrepancies between current and predicted scores in Raven's scale can diagnose mild-moderate dementia with 0.79 accuracy (sensitivity, 0.78; specificity, 0.82).
Despite a hundred years' research, the neuropathology of schizophrenia remains obscure. However, neither can the null hypothesis be sustained--that it is a 'functional' psychosis, a disorder with no structural basis. A number of abnormalities have been identified and confirmed by meta-analysis, including ventricular enlargement and decreased cerebral (cortical and hippocampal) volume. These are characteristic of schizophrenia as a whole, rather than being restricted to a subtype, and are present in first-episode, unmedicated patients. There is considerable evidence for preferential involvement of the temporal lobe and moderate evidence for an alteration in normal cerebral asymmetries. There are several candidates for the histological and molecular correlates of the macroscopic features. The probable proximal explanation for decreased cortical volume is reduced neuropil and neuronal size, rather than a loss of neurons. These morphometric changes are in turn suggestive of alterations in synaptic, dendritic and axonal organization, a view supported by immunocytochemical and ultrastructural findings. Pathology in subcortical structures is not well established, apart from dorsal thalamic nuclei, which are smaller and contain fewer neurons. Other cytoarchitectural features of schizophrenia which are often discussed, notably entorhinal cortex heterotopias and hippocampal neuronal disarray, remain to be confirmed. The phenotype of the affected neuronal and synaptic populations is uncertain. A case can be made for impairment of hippocampal and corticocortical excitatory pathways, but in general the relationship between neurochemical findings (which centre upon dopamine, 5-hydroxytryptamine, glutamate and GABA systems) and the neuropathology of schizophrenia is unclear. Gliosis is not an intrinsic feature; its absence supports, but does not prove, the prevailing hypothesis that schizophrenia is a disorder of prenatal neurodevelopment. The cognitive impairment which frequently accompanies schizophrenia is not due to Alzheimer's disease or any other recognized neurodegenerative disorder. Its basis is unknown. Functional imaging data indicate that the pathophysiology of schizophrenia reflects aberrant activity in, and integration of, the components of distributed circuits involving the prefrontal cortex, hippocampus and certain subcortical structures. It is hypothesized that the neuropathological features represent the anatomical substrate of these functional abnormalities in neural connectivity. Investigation of this proposal is a goal of current neuropathological studies, which must also seek (i) to establish which of the recent histological findings are robust and cardinal, and (ii) to define the relationship of the pathological phenotype with the clinical syndrome, its neurochemistry and its pathogenesis.
Functional brain imaging in humans has revealed task-specific increases in brain activity that are associated with various mental activities. In the same studies, mysterious, task-independent decreases have also frequently been encountered, especially when the tasks of interest have been compared with a passive state, such as simple fixation or eyes closed. These decreases have raised the possibility that there might be a baseline or resting state of brain function involving a specific set of mental operations. We explore this possibility, including the manner in which we might define a baseline and the implications of such a baseline for our understanding of brain function.
Navigation in spatial contexts has been studied in diverse species, yielding insights into underlying neural mechanisms and their phylogenetic progression. Spatial navigation in humans is marked by age-related changes that may carry important implications for understanding cortical development. The emergence of "allocentric" processing, reflecting that ability to use viewer-independent spatial abstractions, represents an important developmental change. We used fMRI to map brain regions engaged during memory-guided navigation in a virtual reality environment in adolescents and adults. Blood oxygen level-dependent (BOLD) signal was monitored in eight adolescents and eight adults in a 1.5-T MRI scanner during three conditions: (1) memory-guided navigation (NAV); (2) arrow-guided navigation (ARROW); and (3) fixation (FIX). We quantified navigation ability during scanning and allocentric memory after scanning, based on subjects' ability to label a previously unseen, aerial view of the town. Adolescents and adults exhibited similar memory-guided navigation ability, but adults exhibited superior allocentric memory ability. Memory-guided navigation ability during scanning correlated with BOLD change between NAV/ARROWS in various regions, including a right frontal and right-anterior medial temporal lobe region. Age group and allocentric memory together explained significant variance in BOLD change in temporoparietal association cortex and the cerebellum, particularly in the left hemisphere. Consistent with developmental models, these findings relate maturation in the coding of spatial information to functional changes in a distributed, left-lateralized neural network.
Finding one's way around an environment and remembering the events that occur within it are crucial cognitive abilities that have been linked to the hippocampus and medial temporal lobes. Our review of neuropsychological, behavioral, and neuroimaging studies of human hippocampal involvement in spatial memory concentrates on three important concepts in this field: spatial frameworks, dimensionality, and orientation and self-motion. We also compare variation in hippocampal structure and function across and within species. We discuss how its spatial role relates to its accepted role in episodic memory. Five related studies use virtual reality to examine these two types of memory in ecologically valid situations. While processing of spatial scenes involves the parahippocampus, the right hippocampus appears particularly involved in memory for locations within an environment, with the left hippocampus more involved in context-dependent episodic or autobiographical memory.
Investigators have recently begun to examine the differential role of subregions of the hippocampus in episodic memory. Two distinct models have gained prominence in the field. One model, outlined by Moser and Moser (Hippocampus 1998;8:608-619), based mainly on animal studies, has proposed that episodic memory is subserved by the posterior two-thirds of the hippocampus alone. A second model, derived by Lepage et al. (Hippocampus 1998;8:313-322) from their review of 52 PET studies, has suggested that the anterior hippocampus is activated by memory encoding while the posterior hippocampus is activated by memory retrieval. Functional magnetic resonance imaging (fMRI) studies have tended to show limited activation in the anteriormost regions of the hippocampus, providing support for the Moser and Moser model. A potential confounding factor in these fMRI studies, however, is that susceptibility artifact may differentially reduce signal in the anterior versus the posterior hippocampus. In the present study, we examined activation differences between hippocampal subregions during encoding and retrieval of words and interpreted our findings within the context of these two models. We also examined the extent to which susceptibility artifact affects the analysis and interpretation of hippocampal activation by demonstrating its differential effect on the anterior versus the posterior hippocampus. Both voxel-by-voxel and region-of-interest analyses were conducted, allowing us to quantify differences between the anterior and posterior aspects of the hippocampus. We detected significant hippocampal activation in both the encoding and retrieval conditions. Our data do not provide evidence for regional anatomic differences in activation between encoding and retrieval. The data do suggest that, even after accounting for susceptibility artifact, both encoding and retrieval of verbal stimuli activate the middle and posterior hippocampus more strongly than the anterior hippocampus. Finally, this study is the first to quantify the effects of susceptibility-induced signal loss on hippocampal activation and suggests that this artifact has significantly biased the interpretation of earlier fMRI studies.
Finding one's way in a large-scale environment may engage different cognitive processes than following a familiar route. The neural bases of these processes were investigated using functional MRI (fMRI). Subjects found their way in one virtual-reality town and followed a well-learned route in another. In a control condition, subjects followed a visible trail. Within subjects, accurate wayfinding activated the right posterior hippocampus. Between-subjects correlations with performance showed that good navigators (i.e., accurate wayfinders) activated the anterior hippocampus during wayfinding and head of caudate during route following. These results coincide with neurophysiological evidence for distinct response (caudate) and place (hippocampal) representations supporting navigation. We argue that the type of representation used influences both performance and concomitant fMRI activation patterns.
This paper puts the case for the hippocampus as being central to the neuropathology and pathophysiology of schizophrenia. The evidence comes from a range of approaches, both in vivo (neuropsychology, structural and functional imaging) and post mortem (histology, morphometry, gene expression, and neurochemistry). Neuropathologically, the main positive findings concern neuronal morphology, organisation, and presynaptic and dendritic parameters. The results are together suggestive of an altered synaptic circuitry or "wiring" within the hippocampus and its extrinsic connections, especially with the prefrontal cortex. These changes plausibly represent the anatomical component of the aberrant functional connectivity that underlies schizophrenia. Glutamatergic pathways are prominently but not exclusively affected. Changes appear somewhat greater in the left hippocampus than the right, and CA1 is relatively uninvolved compared to other subfields. Hippocampal pathology in schizophrenia may be due to genetic factors, aberrant neurodevelopment, and/or abnormal neural plasticity; it is not due to any recognised neurodegenerative process. Hippocampal involvement is likely to be associated with the neuropsychological impairments of schizophrenia rather than with its psychotic symptoms.
Hypofrontality is not a well-replicated finding in schizophrenia either at rest or under conditions of task activation.
Studies comparing whole brain and frontal blood flow/metabolism in schizophrenic patients and normal controls were pooled. Voxel-based studies were also combined to examine the pattern of prefrontal activation in schizophrenia.
Whole brain flow/metabolism was reduced in schizophrenia to only a small extent. Resting and activation frontal flow/metabolism were both reduced with a medium effect size. Duration of illness significantly moderated resting hypofrontality, but the moderating effects of neuroleptic treatment were consistent with an influence on global flow/metabolism only. Pooling of voxel-based studies did not suggest an abnormal pattern of activation in schizophrenia.
Meta-analysis supports resting hypofrontality in schizophrenia. Task-activated hypofrontality is also supported, but there is little from voxel-based studies to suggest that this is associated with an altered pattern of regional functional architecture.
The techniques available for the interrogation and analysis of neuroimaging data have a large influence in determining the flexibility, sensitivity, and scope of neuroimaging experiments. The development of such methodologies has allowed investigators to address scientific questions that could not previously be answered and, as such, has become an important research area in its own right. In this paper, we present a review of the research carried out by the Analysis Group at the Oxford Centre for Functional MRI of the Brain (FMRIB). This research has focussed on the development of new methodologies for the analysis of both structural and functional magnetic resonance imaging data. The majority of the research laid out in this paper has been implemented as freely available software tools within FMRIB's Software Library (FSL).
In rats, the firing sequences observed in hippocampal ensembles during spatial learning are replayed during subsequent sleep, suggesting a role for posttraining sleep periods in the offline processing of spatial memories. Here, using regional cerebral blood flow measurements, we show that, in humans, hippocampal areas that are activated during route learning in a virtual town are likewise activated during subsequent slow wave sleep. Most importantly, we found that the amount of hippocampal activity expressed during slow wave sleep positively correlates with the improvement of performance in route retrieval on the next day. These findings suggest that learning-dependent modulation in hippocampal activity during human sleep reflects the offline processing of recent episodic and spatial memory traces, which eventually leads to the plastic changes underlying the subsequent improvement in performance.
The hippocampus has long been implicated in spatial memory, from work in rodents to imaging and brain lesion studies in humans. However, recent evidence has pointed to the recruitment of areas outside the hippocampus proper on spatial memory tasks, including the parahippocampal gyrus and precuneus, possibly suggesting a more focused role for the hippocampus proper. In this study, a virtual version of the standard rodent spatial memory assessment, the Morris water task, has been employed during fMRI to investigate the differential involvement of these distinct brain areas. Twenty-eight healthy participants completed a block designed version of the virtual Morris water task (vMWT) which consisted of three conditions: (1) a hippocampal dependent condition during which the participants were forced to use distal room cues in the virtual environment to navigate to a hidden platform; (2) a non-hippocampal dependent condition during which participants were to navigate to a visible platform; (3) a fixation period. Activations of the BOLD signal were evident in the hidden condition as compared to the visible condition in the parahippocampal gyrus, precuneus, and fusiform when analyzed using to a blocked analysis. Moreover, this blocked analysis revealed increases in the right hippocampal BOLD signal during fixation. However, when hidden trials were compared to visible trials using a post hoc event-related analysis focused on the beginning of each trial, activations of the right hippocampus are evident. These results support the theory that extra-hippocampal structures contribute to spatial memory behavior and identify a temporally specific involvement of the hippocampus. Furthermore, they substantiate previous results reporting hippocampal BOLD increases during fixation.
Finding our way in a previously learned, ecologically valid environment concurrently involves spatial and contextual cognitive operations. The former process accesses a cognitive map representing the spatial interactions between all paths in the environment. The latter accesses stored associations between landmark objects and their milieu. Here, we aimed at dissociating their neural basis in the context of memory-based virtual navigation. To do so, subjects freely explored a virtual town for 1 h, then were scanned using fMRI while retrieving their way between two locations, under four navigation conditions designed to probe separately or jointly the spatial and contextual memory components. Besides prominent commonalities found in a large hippocampo-neocortical network classically involved in topographical navigation, results yield evidence for a partial dissociation between the brain areas supporting spatial and contextual components of memory-based navigation. Performance-related analyses indicate that hippocampal activity mostly supports the spatial component, whereas parahippocampal activity primarily supports the contextual component. Additionally, the recruitment of contextual memory during navigation was associated with higher frontal, posterior parietal and lateral temporal activity. These results provide evidence for a partial segregation of the neural substrates of two crucial memory components in human navigation, whose combined involvement eventually leads to efficient navigation behavior within a learned environment.
More than three decades of research have demonstrated a role for hippocampal place cells in representation of the spatial environment in the brain. New studies have shown that place cells are part of a broader circuit for dynamic representation of self-location. A key component of this network is the entorhinal grid cells, which, by virtue of their tessellating firing fields, may provide the elements of a path integration-based neural map. Here we review how place cells and grid cells may form the basis for quantitative spatiotemporal representation of places, routes, and associated experiences during behavior and in memory. Because these cell types have some of the most conspicuous behavioral correlates among neurons in nonsensory cortical systems, and because their spatial firing structure reflects computations internally in the system, studies of entorhinal-hippocampal representations may offer considerable insight into general principles of cortical network dynamics.