Navigating complex social interactions along the schizophrenia continuum: Is there a role for social-spatial memory in the formation of long-term social bonds?

Introduction

Psychotic symptoms present along a continuum: severe clinical symptoms of schizophrenia (i.e., positive, negative and cognitive symptoms) characterize the schizophrenia diagnosis, while sub-clinical manifestations of variable severity (i.e., positive, negative and disorganized schizotypy) are fairly common within the general population.¹ The schizophrenia continuum is associated with specific cognitive impairments (e.g., deficits in episodic memory) and social dysfunction (e.g., lower ability to form/maintain a long-lasting pair bond). Accordingly, deficits in episodic memory are reported in people with negative, but not positive, schizotypy,² as well as among clinical patients in different stages of the disease.³ Furthermore, people with negative schizotypy show a reduced probability to get married,⁴ while people with schizophrenia exhibit lower rates of marriage and higher rates of divorce compared to the general population.⁵ Based on the apparent concomitance of these impairments, the following question arises: In the context of schizophrenia continuum, could cognitive impairment predict social dysfunction? Some authors argue about this possibility,⁶ but formal experiments are, in general, lacking. Nevertheless, this phenomenon may manifest in a sexually dimorphic way, since men exhibit more prominent impairments in episodic memory⁷ as well as in pair bonding.⁵ Thus, in the present paper we introduce an overarching hypothesis to explain how episodic memory may contribute to the capacity to engage in complex social interactions −such as pair bonding− within non-pathological and pathological contexts.

Episodic memory may guide pair bonding in men

In a non-pathological perspective, few studies have been explored the participation of episodic memory to influence social decision-making and, by consequence, guide social functioning in daily life activities.⁸

For example, Feldman Hall et al.,⁹ found in healthy subjects that adaptive social decision-making (i.e., interacting with generous individuals and avoiding selfish ones) is based on the individual’s capacity to remember details about previous social experiences, presumably by using episodic memory. Particularly, these authors found that non-adaptive choices are predicted by lower socio-contextual memory (cognitive capacity to associate a person’s identity with its social context, i.e., being generous or selfish during previous experiences). Thus, this evidence suggests that episodic memory could positively influence social functioning within non-pathological contexts.

On the other hand, evidence from pathological contexts suggests that cognitive capacity could predict social dysfunction observed in the schizophrenia continuum, such as the impairment in pair bonding. First, Keefe et al.,¹⁰ found that cognitive capacity was negatively associated with clinical symptom severity. This study showed a higher cognitive capacity among healthy participants, while clinical patients exhibited lower cognition. Similarly, persons with schizotypy who developed clinical symptoms of schizophrenia had lower cognitive capacity in comparison with persons with schizotypy who did not develop the clinical manifestations of the disorder. Based on these findings, DeRosse and Karlsgodt¹ proposed that cognitive capacity negatively predicts symptom severity. In other words, higher cognition could represent a factor of resilience against clinical symptoms. Conversely, lower cognition could favor vulnerability to develop clinical symptoms of schizophrenia. Thus, given that interindividual variability in cognitive capacity was shown to predict symptom severity within the schizophrenia continuum, it is reasonable to expect that cognition might more specifically predict their inherent social dysfunction (i.e., lower ability to form/maintain a long-lasting pair bond).

Furthermore, evidence shows that deficits in episodic memory negatively impact on social functioning.⁶ For example, Lee et al.,³ found in prodromal, first-episode and chronic schizophrenia patients that episodic memory deficits (i.e., social memory and socio-contextual memory) were associated with lower indices of social functioning (i.e., emotional processing and the ability to understand social relationships). Porcelli et al.,¹¹ reported that married individuals with schizophrenia tended to show lower social dysfunction in their daily activities. Similarly, Nuevo et al.,¹² found that a higher number of psychotic symptoms in individuals with schizotypy predicted a lower probability to get married and a higher probability of being separated. Also, these same authors showed that psychotic symptoms were associated with lower social functioning and that cognitive impairment negatively predicted social functioning. Thus, this line of evidence suggests that episodic memory capacity could underlie social functioning, and by consequence, deficits in episodic memory could negatively impact on the capacity to form/maintain a long-lasting pair bond in the context of schizophrenia continuum.

Based on these lines of evidence, we hypothesize that episodic memory could positively influence pair bonding in men within non-pathological and pathological contexts. Thus, men that exhibit clinical symptoms of schizophrenia or sub-clinical manifestations associated with negative schizotypy tend to remain single, never marry, or are more likely to divorce, indicating a diminished ability to form/maintain a long-lasting pair bond. Thus, their capacity for daily social functioning would be negatively affected by their lower capacity to remember details about previous social experiences, presumably due to discrete impairments in episodic memory (i.e., impaired conscious recollection).

Testing the overarching hypothesis by using a comparative approach

Recently, in our laboratory we decided to test the overarching hypothesis by using “From the Clinic to the Laboratory and Back Again Approach”.¹³ Basically, we construct a “human hypothesis” based on the clinical evidence; this hypothesis is tested in the laboratory, by using a comparative animal model approach. Finally, the results of comparative studies are interpreted and considered in the context of the human phenomenon, generating hypotheses to be tested in human populations. Thus, we use the prairie vole (Microtus ochrogaster) as a model organism to testing the overarching hypothesis. This rodent has been extensively studied to understand biological features of social bonding, since the behavioral specializations observed in the prairie vole (i.e., formation and maintenance of long-lasting pair bond in natural, semi-natural and laboratory conditions).^14,15 Furthermore, some models theorize that male prairie voles’ episodic memory could guide social decision-making within the context of long-lasting pair bond to enhance ecological adequation and maximize reproductive success.¹⁵ For example, Young’s model suggests that social memory, a specific component of episodic memory, allows for partner recognition, which is important during pair bond formation.¹⁶ On the other hand, Ophir’s model suggests that social-spatial memory, other component of episodic memory, promotes mate guarding to enable pair bond maintenance.^15,17

Based on our hypothesis, we first predicted that a pharmacologically-induced deficit in episodic memory would impair pair bond formation in the male prairie vole as a model for social dysfunction of schizophrenia. In a recent study we showed that sub-chronic administration of MK-801, an NMDA receptor antagonist, impaired voles’ social memory capacity. Interestingly, these cognitive impairments negatively impacted on the males’ ability to form a pair bond.¹⁸ These results have translational relevance to human schizophrenia, since clinical symptoms of schizophrenia, including episodic memory impairments, are linked to a general hypofunction of the NMDA receptor.¹⁹ Indeed, repeated administration of NMDA receptor antagonists induces deficits in episodic memory, for example, MK-801 in rodents²⁰ and in the context of chronic ketamine abuse in humans.²¹ Thus, an experimental manipulation that has been shown to induce a pathophysiological phenotype similar to schizophrenia in rodent models, reproduces in the prairie vole a discrete dysfunction in social behavior reminiscent of that observed in men with schizophrenia, as was predicted by our hypothesis. Considering this result, we propose that the male prairie vole could be a preclinical model to test potential pro-cognitive drugs that might improve social functioning in schizophrenia, given that current pharmacological development in schizophrenia is focused on improving daily social functioning, rather than developing symptom management strategies.²²

Secondly, schizotypy resembles a predisposition “state” to develop the schizophrenia symptoms,²³ and between 10 to 25% of psychotic experiences are not transitory.²⁴ Thus, we examined whether intrinsic (i.e., cognition) and extrinsic (i.e., reproduction) factors could promote resilience/vulnerability on certain individuals. Recently, we found in a separate study (Basurto et al., in preparation) that interindividual variation in episodic memory (i.e., social-spatial memory) positively predicted pair bond maintenance in the male prairie vole. In respect thereof, individuals that displayed higher social-spatial memory capacity tended to be pair bonded, while those with lower social-spatial memory did not exhibit a pair bond. Intriguing similarities are observed in men within the continuum of schizophrenia (i.e., lower episodic memory predicts impaired pair bonding), as was described above. On the other hand, we propose that successful reproduction could represent a source of resilience in the context of the schizophrenia continuum, since evidence in healthy humans showed that successful reproduction increases cognition (i.e., working memory²⁵) and promotes stability in long-lasting pair bonds.²⁶ By contrast, decreased rates of reproduction are observed in the schizophrenia continuum, mostly in men,²⁷ along with cognitive and pair bond impairments. Results obtained in the male prairie vole demonstrated that successful reproduction was associated with increased episodic memory, and independently promoted pair bond maintenance. Interestingly, non-reproductive male voles exhibit impairments in episodic memory and tend to not exhibit a pair bond, similarly to men with increased vulnerability to develop clinical manifestations of schizophrenia (see above). Based on this evidence, we speculate that cognitive capacity guides complex interactions but also predicts symptom severity within the context of schizophrenia continuum. Also, we address the idea that successful reproduction could represent a source of resilience against developing clinical manifestations of schizophrenia in men, mediated by improved cognition. However, these assumptions need future validation by formal experiments.

Conclusions and perspectives

Based on non-pathological and pathological evidence, we hypothesize that episodic memory could positively influence pair bond formation and maintenance in men in the context of schizophrenia continuum. Comparative studies support this hypothesis, since deficits in episodic memory (induced as consequence of chronic NMDA receptor antagonism or unsuccessful reproduction) negatively impacted the ability to form and maintain a pair bond in the male prairie vole. Based on this evidence, we speculate that cognition shapes pair bonding and predicts symptom severity within the context of schizophrenia continuum. Furthermore, we address the idea that extrinsic factors (i.e., reproduction) can influence intrinsic individuals’ factors (i.e., cognition) to promote resilience to developing clinical manifestations of schizophrenia in men. These new insights need to be tested in humans.