Evidence for grid-cell-like activity in the time domain.

The relation between the processing of space and time in the brain has been an enduring cross-disciplinary question. Grid cells have been recognized as a hallmark of the mammalian navigation system, with recent studies attesting to their involvement in the organization of conceptual knowledge in humans. To determine whether grid-cell-like representations support temporal processing, we asked subjects to mentally simulate changes in age and time-of-day, each constituting "trajectory" in an age-day space, while undergoing fMRI. We found that grid-cell-like representations supported trajecting across this age-day space. Furthermore, brain regions concurrently coding past-to-future orientation positively modulated the magnitude of grid-cell-like representation in the left entorhinal cortex. Finally, our findings suggest that temporal processing may be supported by spatially modulated systems, and that innate regularities of abstract domains may interface and alter grid-cell-like representations, similarly to spatial geometry.

Lost in space(s): Multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty and the bedrock of the neurologic examination. Orientation is defined as the alignment between an individual's internal representation and the external world in the spatial, temporal, and social domains. While spatial disorientation is a recognized hallmark of Alzheimer's disease (AD), little is known about disorientation beyond space in AD. This study aimed to explore disorientation in spatial, temporal, and social domains along the AD continuum. Fifty-one participants along the AD continuum performed an ecological orientation task in the spatial, temporal, and social domains while undergoing functional MRI. Disorientation in AD followed a three-way association between orientation domain, brain region, and disease stage. Specifically, patients with early amnestic mild cognitive impairment exhibited spatio-temporal disorientation and reduced brain activity in temporoparietal regions, while patients with AD dementia showed additional social disorientation and reduced brain activity in frontoparietal regions. Furthermore, patterns of hypoactivation overlapped different subnetworks of the default mode network, patterns of fluorodeoxyglucose hypometabolism, and cortical atrophy characteristic of AD. Our results suggest that AD may encompass a disorder of orientation, characterized by a biphasic process manifesting as early spatio-temporal and late social disorientation. As such, disorientation may offer a unique window into the clinicopathological progression of AD. SIGNIFICANCE STATEMENT: Despite extensive research into Alzheimer's disease (AD), its core cognitive deficit remains a matter of debate. In this study, we investigated whether orientation, defined as the ability to align internal representations with the external world in spatial, temporal, and social domains, constitutes a core cognitive deficit in AD. To do so, we used PET-fMRI imaging to collect behavioral, functional, and metabolic data from 51 participants along the AD continuum. Our findings suggest that AD may constitute a disorder of orientation, characterized by an early spatio-temporal disorientation and followed by late social disorientation, manifesting in task-evoked and neurodegenerative changes. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD and as such could greatly benefit disease diagnosis, monitoring, and evaluation of treatment response.

The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

A neural circuit for spatial orientation derived from brain lesions.

There is disagreement regarding the major components of the brain network supporting spatial cognition. To address this issue, we applied a lesion mapping approach to the clinical phenomenon of topographical disorientation. Topographical disorientation is the inability to maintain accurate knowledge about the physical environment and use it for navigation. A review of published topographical disorientation cases identified 65 different lesion sites. Our lesion mapping analysis yielded a topographical disorientation brain map encompassing the classic regions of the navigation network: medial parietal, medial temporal, and temporo-parietal cortices. We also identified a ventromedial region of the prefrontal cortex, which has been absent from prior descriptions of this network. Moreover, we revealed that the regions mapped are correlated with the Default Mode Network sub-network C. Taken together, this study provides causal evidence for the distribution of the spatial cognitive system, demarking the major components and identifying novel regions.

Lost in space(s): multimodal neuroimaging of disorientation along the Alzheimer's disease continuum.

Orientation is a fundamental cognitive faculty, allowing the behaving self to link his/her current state to their internal representations of the external world. Once exclusively linked to knowledge of the current place and present time, in recent years, the concept of orientation has evolved to include processing of social, temporal, and abstract relations. Concordantly with the growing focus on orientation, spatial disorientation has been increasingly recognized as a hallmark symptom of Alzheimer's disease (AD). However, few studies have sought to explore disorientation along the AD continuum beyond the spatial domain. 51 participants along the AD continuum performed an orientation task in the spatial, temporal and social domains. Under functional magnetic resonance imaging (fMRI), participants determined which of two familiar places/events/people is geographically/ chronologically/ socially closer to them, respectively. A series of analyses revealed disorientation along the AD- continuum to follow a three-way association between (1) orientation domain, (2) brain region, and (3) disease stage. Specifically, participants with MCI exhibited impaired spatio-temporal orientation and reduced task-evoked activity in temporoparietal regions, while participants with AD dementia exhibited impaired social orientation and reduced task-evoked activity in frontoparietal regions. Furthermore, these patterns of hypoactivation coincided with Default Mode Network (DMN) sub-networks, with spatio-temporal orientation activation overlapping DMN-C and social orientation with DMN-A. Finally, these patterns of disorientation- associated hypoactivations coincided with patterns of fluorodeoxyglucose (FDG) hypometabolism and cortical atrophy characteristic to AD-dementia. Taken together, our results suggest that AD may constitute a disorder of orientation, characterized by a biphasic process as (1) early spatio-temporal and (2) late social disorientation, concurrently manifesting in task-evoked and neurodegenerative changes in temporoparietal and parieto-frontal brain networks, respectively. We propose that a profile of disorientation across multiple domains offers a unique window into the progression of AD.

Consciousness, Memory, and the Human Self: Commentary on "Consciousness as a Memory System" by Budson et al (2022).

Philosophical theories have attempted to shed light on the intricate relationships between consciousness and memory since long before this became a major theme in psychology and neuroscience. In the December 2022 issue of Cognitive and Behavioral Neurology , Budson, Richman, and Kensinger (2022) introduced a comprehensive theoretical framework pertaining to the origins of consciousness in relation to the memory system, its implications on our real-time perception of the world, and the neuroanatomical correlates underlying these phenomena. Throughout their paper, Budson et al (2022) focus on their theory's explanatory value regarding several clinical syndromes and experimental findings. In this commentary, we first summarize the theory presented by Budson and colleagues (2022). Then, we suggest a complementary approach of studying the relationships between consciousness and memory through the concept of the human self and its protracted representation through time (so-called mental time travel). Finally, we elaborate on Budson and colleagues' (2022) neuroanatomical explanation to their theory and suggest that adding the concepts of brain networks and cortical gradients may contribute to their theory's interpretability.

Brain System for Social Categorization by Narrative Roles.

The cognitive system applies categorical thinking to facilitate perception of the rich environment around us. In person cognition, research has focused on the roles of gender, race, age, or appearance in social categorical thinking. Here we investigated how narrative roles, as portrayed by different cinematic characters, are categorized in the neurocognitive system. Under functional MRI, 17 human participants (7 females) were asked to make different judgments regarding personality traits of 16 renowned cinematic characters representing four roles: hero, sidekick, mentor, and villain. Classification analysis showed a brain network, comprising the dorsal medial prefrontal cortex, the precuneus and the temporoparietal junction bilaterally, and the left occipital face area (OFA), to discriminate among the four roles. No such classification was found between other individual attributes including age or the associated film. Moreover, regions overlapping the default mode network (DMN) were found to better discriminate between roles, rather than the individual characters, while the OFA was found to better discriminate between individuals. These results demonstrate the inherent role of roles in person cognition, and suggest an intimate relation between roles categorization and self-referential activity.SIGNIFICANCE STATEMENT Social categorization, the assignment of different people in our social network to subgroups, is a powerful strategy in social cognition. How is this managed by the brain? We provide evidence that different characters from different stories, representing similar roles in their corresponding narrative, elicit similar brain activation patterns, as revealed by functional MRI. Unlike previous studies of social categorization, these brain activations were similar to those elicited by social cognition rather than face processing, and included regions at the prefrontal cortex, the precuneus, and the temporoparietal junction. The identified brain network significantly overlapped the default mode network. We suggest that social categorization by roles is fundamental to the cognitive system, relying on brain regions related to social cognition.

Transforming social perspectives with cognitive maps.

Growing evidence suggests that cognitive maps represent relations between social knowledge similar to how spatial locations are represented in an environment. Notably, the extant human medial temporal lobe literature assumes associations between social stimuli follow a linear associative mapping from an egocentric viewpoint to a cognitive map. Yet, this form of associative social memory does not account for a core phenomenon of social interactions in which social knowledge learned via comparisons to the self, other individuals or social networks are assimilated within a single frame of reference. We argue that hippocampal-entorhinal coordinate transformations, known to integrate egocentric and allocentric spatial cues, inform social perspective switching between the self and others. We present evidence that the hippocampal formation helps inform social interactions by relating self vs other social attribute comparisons to society in general, which can afford rapid and flexible assimilation of knowledge about the relationship between the self and social networks of varying proximities. We conclude by discussing the ramifications of cognitive maps in aiding this social perspective transformation process in states of health and disease.

Mental travel in the person domain.

"Mental travel" is a cognitive concept embodying the human capacity to intentionally disengage from the here and now, and mentally experience the world from different perspectives. We explored how individuals mentally "travel" to the point of view (POV) of other people in varying levels of personal closeness and from these perspectives process these people's social network. Under fMRI, participants were asked to "project" themselves to the POVs of four different people: a close other, a nonclose other, a famous-person, and their own-self, and rate the level of affiliation (closeness) to different individuals in the respective social network. Participants were always faster making judgments from their own POV compared with other POVs (self-projection effect) and for people who were personally closer to their adopted POV (social-distance effect). Brain activity at the medial prefrontal and anterior cingulate cortex in the self-POV was higher, compared with all other conditions. Activity at the right temporoparietal junction and medial parietal cortex was found to distinguish between the personally related (self, close, and nonclose others) and unrelated (famous-person) people. No difference was found between mental travel to the POVs of close and nonclose others. Regardless of POV, the precuneus, anterior cingulate cortex, prefrontal cortex, and temporoparietal junction distinguished between close and distant individuals within the different social networks. Representational similarity analysis implicated the left retrosplenial cortex as crucial for social distance processing across all POVs. These distinctions suggest several constraints regarding our ability to adopt others' POV and process not only ours but also other people's social networks and stress the importance of proximity in social cognition.NEW & NOTEWORTHY Mental-travel, the ability to mentally imagine oneself in a different place and time, is a fundamental cognitive concept. Investigation of mental-travel in the social domain under fMRI revealed that a network of brain regions, largely overlapping the default-mode-network, is responsible for "traveling" to points of view of different others; moreover, this network distinguishes between closer and less-close others, suggesting that mental-travel is a rich dynamical process, encompassing individuals in different proximities and these individuals' social network.

Agency, Ownership and the Potential Space.

The potential space, the space between the experiencer and the experience, is at the heart of Winnicott's theory. The concepts of agency of one's actions and ownership of one's experience have been recently applied to such a space lying in between the experiencing self and the mental (cognitive) map she creates, representing her surroundings. Agency is defined as "the sense that I am the one who is generating the experience represented on a mental map", while ownership is defined as "the sense that I am the one who is undergoing an experience, represented on a mental map". Here these concepts are introduced and applied to five main realizations of Winnicott's potential space: Playing, transitional phenomena, the therapeutic space, culture and creativity. Through theoretical constructs and clinical analyses, it is shown how agency and ownership, and their mutual interrelations, may help to better understand Winnicott's theory with implications to clinical practice.

Brain Coding of Social Network Structure.

Humans have large social networks, with hundreds of interacting individuals. How does the brain represent the complex connectivity structure of these networks? Here we used social media (Facebook) data to objectively map participants' real-life social networks. We then used representational similarity analysis (RSA) of functional magnetic resonance imaging (fMRI) activity patterns to investigate the neural coding of these social networks as participants reflected on each individual. We found coding of social network distances in the default-mode network (medial prefrontal, medial parietal, and lateral parietal cortices). When using partial correlation RSA to control for other factors that can be correlated to social distance (personal affiliation, personality traits. and visual appearance, as subjectively rated by the participants), we found that social network distance information was uniquely coded in the retrosplenial complex, a region involved in spatial processing. In contrast, information on individuals' personal affiliation to the participants and personality traits was found in the medial parietal and prefrontal cortices, respectively. These findings demonstrate a cortical division between representations of non-self-referenced (allocentric) social network structure, self-referenced (egocentric) social distance, and trait-based social knowledge.SIGNIFICANCE STATEMENT Each of us has a social network composed of hundreds of individuals, with different characteristics and different relations among them. How does our brain represent this complexity? To find out, we mapped participants' social connections using Facebook data and then asked them to think about individuals from their network while undergoing functional MRI scanning. We found that the position of individuals within the social network, as well as their affiliation to the participant, are mapped in the retrosplenial complex, a region involved in spatial processing. Individuals' personality traits were coded in another region, the medial prefrontal cortex. Our findings demonstrate a neural dissociation among different aspects of social knowledge and suggest a link between spatial and social cognitive mapping.

The 'creatures' of the human cortical somatosensory system.

Penfield's description of the 'homunculus', a 'grotesque creature' with large lips and hands and small trunk and legs depicting the representation of body-parts within the primary somatosensory cortex (S1), is one of the most prominent contributions to the neurosciences. Since then, numerous studies have identified additional body-parts representations outside of S1. Nevertheless, it has been implicitly assumed that S1's homunculus is representative of the entire somatosensory cortex. Therefore, the distribution of body-parts representations in other brain regions, the property that gave Penfield's homunculus its famous 'grotesque' appearance, has been overlooked. We used whole-body somatosensory stimulation, functional MRI and a new cortical parcellation to quantify the organization of the cortical somatosensory representation. Our analysis showed first, an extensive somatosensory response over the cortex; and second, that the proportional representation of body parts differs substantially between major neuroanatomical regions and from S1, with, for instance, much larger trunk representation at higher brain regions, potentially in relation to the regions' functional specialization. These results extend Penfield's initial findings to the higher level of somatosensory processing and suggest a major role for somatosensation in human cognition.

Processing of Different Temporal Scales in the Human Brain.

While recalling life events, we reexperience events of different durations, ranging across varying temporal scales, from several minutes to years. However, the brain mechanisms underlying temporal cognition are usually investigated only in small-scale periods-milliseconds to minutes. Are the same neurocognitive systems used to organize memory at different temporal scales? Here, we asked participants to compare temporal distances (time elapsed) to personal events at four different temporal scales (hour, day, week, and month) under fMRI. Cortical activity showed temporal scale sensitivity at the medial and lateral parts of the parietal lobe, bilaterally. Activity at the medial parietal cortex also showed a gradual progression from large- to small-scale processing, along a posterior-anterior axis. Interestingly, no sensitivity was found along the hippocampal long axis. In the medial scale-sensitive region, most of the voxels were preferentially active for the larger scale (month), and in the lateral region, scale selectivity was higher for the smallest scale (hour). These results demonstrate how scale-selective activity characterizes autobiographical memory processing and may provide a basis for understanding how the human brain processes and integrates experiences across timescales in a hierarchical manner.

Hierarchical cortical gradients in somatosensory processing.

Sensory information is processed in the visual cortex in distinct streams of different anatomical and functional properties. A comparable organizational principle has also been proposed to underlie auditory processing. This raises the question of whether a similar principle characterize the somatosensory domain. One property of a cortical stream is a hierarchical organization of the neuronal response properties along an anatomically distinct pathway. Indeed, several hierarchies between specific somatosensory cortical regions have been identified, primarily using electrophysiology, in non-human primates. However, it has been unclear how these local hierarchies are organized throughout the cortex. Here we used phase-encoded bilateral full-body light touch stimulation in healthy humans under functional MRI to study the large-scale organization of hierarchies in the somatosensory domain. We quantified two measures of hierarchy of BOLD responses, selectivity and laterality. We measured how selectivity and laterality change as we move away from the central sulcus within four gross anatomically-distinct regions. We found that both selectivity and laterality decrease in three directions: parietal, posteriorly along the parietal lobe, frontal, anteriorly along the frontal lobe and medial, inferiorly-anteriorly along the medial wall. The decline of selectivity and laterality along these directions provides evidence for hierarchical gradients. In view of the anatomical segregation of these three directions, the multiplicity of body representations in each region and the hierarchical gradients in our findings, we propose that as in the visual and auditory domains, these directions are streams of somatosensory information processing.

The radiation of autonoetic consciousness in cognitive neuroscience: A functional neuroanatomy perspective.

One of Endel Tulving's most important contributions to memory research is the coupling of self-knowing consciousness (or "autonoesis") with episodic memory. According to Tulving, autonoetic episodic memory enables the uniquely human neurocognitive operation of "mental time travel", which is the ability to deliberately "project" oneself to a specific time and place to remember personally experienced events that occurred in the past and simulate personal happenings that may occur in the future. These ideas ignited an explosion of research in the years to follow, leading to the development of several related concepts and theories regarding the role of the human self in memory and prospection. In this paper, we first explore the expansion of the concept of autonoetic consciousness in the cognitive neuroscience literature as well as the formulation of derivative concepts and theories. Subsequently, we review such concepts and theories including episodic memory, mental time travel, episodic simulation, scene construction and self-projection. In view of Tulving's emphasis of the temporal and spatial context of the experience, we also review the cognitive operation involved in "travel" (or "projection") in these domains as well as in the social domain. We describe the underlying brain networks and processes involved, their overlapping activations and involvement in giving rise to the experience. Meta-analysis of studies investigating the underlying functional neuroanatomy of these theories revealed main overlapping activations in sub-regions of the medial prefrontal cortex, the precuneus, retrosplenial cortex, temporoparietal junction and medial temporal lobe. Dissection of these results enables to infer and quantify the interrelations in between the different theories as well as with respect to Tulving's original ideas.

A Novel Integrative Psychotherapy for Psychogenic Nonepileptic Seizures Based on the Biopsychosocial Model: A Retrospective Pilot Outcome Study.

BACKGROUND: Psychogenic nonepileptic seizures (PNES) represent one of the most sizable treatment challenges in neuropsychiatry. Although the underlying mechanism is far from being understood, several interventions have been suggested. However, patients with comorbid psychiatric diagnoses and epilepsy are excluded from most intervention studies. OBJECTIVE: To To present a within-group posttreatment vs pretreatment study representing the retrospective clinical results of an integrative psychotherapy model. METHODS: We present the clinical results of 22 patients with PNES diagnosed in an epilepsy center and treated in our neuropsychiatry clinic using an integrative rehabilitative psychotherapy. Therapy included presenting the diagnosis, psychoeducation, seizure reduction behavioral techniques, and coping with past and present stressors. Insomuch as integrative biopsychosocial psychotherapy is based on an individualized treatment protocol for each patient, treatment was individualized and case specific. RESULTS: By the end of treatment, 36% of patients had become seizure free and a further 54% achieved a major seizure reduction (reduction of more than 70%). Seventy-two percent of patients kept at least 70% seizure reduction at follow-up. Global Assessment of Functioning scores improved from a mean of 43.09 to a mean of 72.81 at the end of treatment and 69.72 at follow-up. In addition, we present 3 case descriptions that emphasize the individualized nature of psychotherapeutic decisions. CONCLUSIONS: Our results support the feasibility and effectiveness of biopsychosocial based integrative psychotherapy for PNES and set principles for future treatment and prospective clinical trials in the field of individualized psychotherapy.

A unified brain system of orientation and its disruption in Alzheimer's disease.

OBJECTIVE: To investigate whether a unified brain system manages one's orientation to different places, events and people in one's environment, and test the hypothesis that failure of this system (disorientation) is an early sign of Alzheimer's disease (AD). METHODS: A total of 46 participants (patients along the AD continuum and cognitively normal control subjects) were tested in a personalized, ecologically valid task of orientation relating to the participant's own world in space, time and person under high-density electroencephalography. As a first step, we used evoked potential mapping to search for brain topography correlated with participants' performance in orientating themselves to different places (space), events (time) and people (person) (Experiment 1). We then compared behavioral and electrophysiological changes in patients along the AD continuum (Experiment 2). RESULTS: We identified a specific brain topography ("orientation map") that was active for orientation in space, time and person in correlation to participants' performance. Both performance and the map's strength gradually decreased from health to mild cognitive impairment (MCI) and from MCI to AD. Another map, immediately preceding the orientation map, showed the longest activity in patients with MCI, significantly more than both patients with AD and cognitively normal controls. INTERPRETATION: Our findings demonstrate that the same brain topography accounts for orientation in the different domains of space, time and person and provide a nexus between deterioration in patients' orientation with the aggravation of Alzheimer's disease.

Processing of different spatial scales in the human brain.

Humans navigate across a range of spatial scales, from rooms to continents, but the brain systems underlying spatial cognition are usually investigated only in small-scale environments. Do the same brain systems represent and process larger spaces? Here we asked subjects to compare distances between real-world items at six different spatial scales (room, building, neighborhood, city, country, continent) under functional MRI. Cortical activity showed a gradual progression from small to large scale processing, along three gradients extending anteriorly from the parahippocampal place area (PPA), retrosplenial complex (RSC) and occipital place area (OPA), and along the hippocampus posterior-anterior axis. Each of the cortical gradients overlapped with the visual system posteriorly and the default-mode network (DMN) anteriorly. These results suggest a progression from concrete to abstract processing with increasing spatial scale, and offer a new organizational framework for the brain's spatial system, that may also apply to conceptual spaces beyond the spatial domain.

Memory and motor control in patients with psychogenic nonepileptic seizures.

Psychogenic nonepileptic seizures (PNES) are of the most elusive phenomena in epileptology. Patients with PNES present episodes resembling epileptic seizures in their semiology yet lacking the underlying epileptic brain activity. These episodes are assumed to be related to psychological distress from past trauma, yet the underlying mechanism of this manifestation is still unknown. Using resting-state functional magnetic resonance imaging (fMRI), we investigated functional connectivity changes within and between large-scale brain networks in 9 patients with PNES, compared with a group of 13 age- and gender-matched healthy controls. Functional magnetic resonance imaging analyses identified functional connectivity disturbances between the medial temporal lobe (MTL) and the sensorimotor cortex and between the MTL and ventral attention networks in patients with PNES. Within network connectivity reduction was found within the visual network. Our findings suggest that PNES relate to changes in connectivity in between areas that are involved in memory processing and motor activity and attention control. These results may shed new light on the way by which traumatic memories may relate to PNES.

The neuroanatomy of age perception.

The concept of age is a fundamental aspect of mental life. However, it is not clear whether age is more an autobiographical detail we remember, a number indicating the years we live, or an inherent part of our subjective self-perception. An insight may be inferred from the underlying neuroanatomy. To investigate the neuroanatomical basis of age perception, we used lesion analysis in 7 patients with age-disorientation due to acute stroke, as compared to a control group of 9 age-oriented patients. Age-disoriented patients underestimated their age by 17.8±5.0 years. Lesion analysis indicated main regions of overlap in the insula, as well as the rolandic operculum and the supramarginal gyrus, predominantly in the left hemisphere, as compared to stroke patients without age-disorientation. Since these regions are involved in the cognitive functions of self-referenced time-processing, including its emotional aspects, our data suggest that these functions are intimately related to age perception.