Associations of Perceived Stress and Psychological Resilience With Cognition and a Modifiable Dementia Risk Score in Middle-Aged Adults.

OBJECTIVES: Psychological stress has been proposed as a risk factor for cognitive impairment and dementia. However, it remains unclear how an individual's stress-coping ability (i.e., psychological resilience) is related to cognition. This cross-sectional study investigated whether perceived stress and psychological resilience were associated with cognition and a modifiable dementia risk score in a large community-based sample of cognitively normal adults. The moderating effect of psychological resilience was also examined. METHODS: Participants (mean age = 57 ± 7 years) enrolled in the web-based Healthy Brain Project completed the Perceived Stress Scale and the Connor-Davidson Resilience Scale. Domains of attention and working memory were assessed using the Cogstate Brief Battery (n = 1,709), and associative memory was assessed using the Cambridge Neuropsychological Test Automated Battery (n = 1,522). Dementia risk was estimated for 1,913 participants using a modified version of the Cardiovascular Risk Factors, Aging, and Incidence of Dementia dementia risk score, calculated using only readily modifiable dementia risk factors. RESULTS: In separate linear regression analyses adjusted for age, sex, education, and race, greater levels of perceived stress and lower levels of psychological resilience were associated with poorer performance across all cognitive domains, as well as a higher modifiable dementia risk score. Psychological resilience did not moderate the effect of perceived stress on cognition or the dementia risk score. DISCUSSION: Higher perceived stress and lower resilience were associated with poorer cognition and a greater burden of modifiable dementia risk factors. Intervention studies are required to determine if lowering stress and building resilience can mitigate cognitive deficits and reduce dementia risk.

Psychological distress and gender predict cognitive complaint after adult civilian mild traumatic brain injury in pre-morbidly healthy adults.

Subjective cognitive symptoms are common after mild traumatic brain injury (mTBI), and are associated with important outcome factors including return to work. This study examined self-reported cognitive symptoms in mTBI and trauma controls (TCs), and explored psychological distress and gender as predictors of these symptoms. Pre-morbidly healthy adults with mTBI (n = 68) and general trauma (n = 40) were prospectively recruited from inpatient hospital wards and assessed 6-10 weeks post-injury. Primary measures included self-reported cognitive symptoms, post-concussion symptoms, and psychological distress. Groups were matched on all background variables, including objective cognitive performance. Within this context, subjective cognitive symptoms were significantly elevated after mTBI relative to TCs (t = 3.396, p = .001). In contrast, there was no difference in post-concussion symptoms between groups (t = 1.275, p = .206). Psychological distress (ß = .536, p < .001) and gender (ß = .253, p = .012) predicted subjective cognitive symptoms in mTBI, with females and those with higher distress reporting greater symptoms. Unlike general post-concussion symptoms, subjective cognitive symptoms were elevated after mTBI relative to TCs, suggesting that mTBI-specific factors underly this elevation. Females and individuals with high psychological distress are important subgroups to consider for potential intervention following mTBI.

Vague retellings of personal narratives in temporal lobe epilepsy.

PURPOSE: Aside from deficits identified in single-word level retrieval, individuals with temporal lobe epilepsy (TLE) exhibit clinical oddities, such as circumstantiality in their language production. Circumstantiality refers to the use of language which is pedantic, repetitive, and overly detailed. This becomes particularly evident when elicitation tasks impose minimal structure, or when impersonal narratives are retold over consecutive occasions. Personal reminiscence is highly specific and localised in time, placing unique demands on cognitive-linguistic systems. It is hypothesised that the nature of this elicitation paradigm will produce a unique psycholinguistic phenotype in those with TLE. Among controls there is a compression of output for impersonal narratives, meaning that they use fewer words over less time and are more fluent. The opposite effect is observed when personal narratives are retold. METHODS: To investigate the micro- and macrolinguistic processes underpinning personal discourse production in TLE, we examined the elicited language output of 15 surgically naïve individuals with TLE and 14 healthy controls. Participants were asked to recall and re-tell an autobiographical memory on four immediately consecutive occasions, representing an alternative unstructured elicitation. Following transcription and coding of output, a detailed multi-level discourse analysis of output volume, fluency, cohesion, and coherence was conducted. RESULTS: As anticipated, a distinctly different pattern emerged in TLE when compared with controls who did not compress their output volume across repetitions but instead produced greater novelty, and a more coherent and refined account over time. Individuals with TLE consistently told a less distinct story across repetitions, with disturbances in fluency, cohesion, and coherence. CONCLUSION: This reflects a reduced capacity to produce a coherent mental representation, in all likelihood related to the neurolinguistic demands of recalling and retelling specific personal events.

Verbosity with retelling: Narrative discourse production in temporal lobe epilepsy.

To examine micro- and macrolinguistic underpinnings of circumstantiality in temporal lobe epilepsy (TLE), we examined the elicited narrative output of 15 individuals with TLE and 14 controls. To replicate and extend Field and colleagues' (2000) work, participants were asked to produce five immediately consecutive elicitations of an eight-frame cartoon "Cowboy Story" (Joanette et al., 1986). Following transcription and coding, detailed multi-level discourse analysis demonstrated a typical pattern of compression in controls. The narratives produced by individuals with TLE were less fluent, cohesive, and coherent across trials: producing fewer novel units and more repetitive and extraneous content. Significant group by trial interactions in sample length, spontaneous duration, and statements, were not explained by seizure burden, age, or lexical retrieval deficits. These findings suggest that they do not benefit from repeated engagement with a narrative in the same manner as controls. Disturbed social cognition and pragmatics in TLE might underpin communication inefficiencies.

Frequency and extent of cognitive complaint following adult civilian mild traumatic brain injury: a systematic review and meta-analysis.

OBJECTIVE: Cognitive symptoms are associated with return to work, healthcare use and quality of life after mild traumatic brain injury (mTBI). Additionally, while overall 'post-concussion' symptoms are often present at similar levels in mTBI and control groups, cognitive complaints may be specifically elevated in mTBI. A systematic review and meta-analysis was conducted to investigate the frequency and extent of cognitive complaints following adult civilian mTBI, and compare it to the frequency and extent of complaints in control populations (PROSPERO: CRD42020151284). METHOD: This review included studies published up to March 2022. Thirteen studies were included in the systematic review, and six were included in the meta-analysis. Data extraction and quality assessment were conducted by two independent reviewers. RESULTS: Cognitive complaints are common after mTBI, although reported rates differed greatly across studies. Results suggested that mTBI groups report cognitive complaints to a significantly greater extent than control groups (Hedges' g = 0.85, 95% CI 0.31-1.40, p = .0102). Heterogeneity between studies was high (τ2 = 0.20, 95% CI 0.04-1.58; I2 = 75.0%, 95% CI 43.4%-89.0%). Between-group differences in symptom reporting were most often found when healthy rather than injured controls were employed. CONCLUSIONS: Cognitive complaints are consistently reported after mTBI, and are present at greater levels in mTBI patients than in controls. Despite the importance of these complaints, including in regards to return to work, healthcare use and quality of life, there has been limited research in this area, and heterogeneity in research methodology is common.

The Spatial Learning Task of Lhermitte and Signoret (1972): Normative Data in Adults Aged 18-45.

Objective: The Spatial Learning Task of Lhermitte and Signoret is an object-location arbitrary associative learning task. The task was originally developed to evaluate adults with severe amnesia. It is currently used in populations where the memory system either is not yet fully developed or where it has been compromised (e.g. epilepsy, traumatic brain injury, electroconvulsive therapy, cerebrovascular disease and dementia). Normative data have been published for paediatric cohorts and for older adults, however no data exist for the intervening adult years. Method: Here, we address this gap, collecting normative data from 101 adults aged 18-45. Results: Our data indicate that performance on the Spatial Learning Task is not influenced by age, gender, level of education or overall IQ. Less than 10% of the variance in learning scores is associated with variability in verbal memory. Ninety percent of participants achieved perfect scores on two successive trials (T2Cr) within five or fewer trials on the Spatial Learning Task. A T2Cr score of 6 is suggestive of impairment and a T2Cr score of 7 or more is statistically abnormal. Conclusion: These data expand the clinical utility of the Spatial Learning Task in the adult population. Future work should examine performance in lower IQ cohorts, including intellectual disability, and explore sensitivity to disease factors such as laterality of mesial temporal lobe damage.

Memory Complaints in Healthy Middle-Aged Adults Are Not Associated with Memory or Sustained Attention Performance.

OBJECTIVE: To examine the associations between the number and type of memory complaints with memory and sustained attention performance in healthy middle-aged adults. METHOD: Sixty-six healthy individuals aged 35-64 years (Mage = 47.73 years) were administered the seven Questions, Rey Auditory Verbal Learning Test, Sustained Attention to Response Task, and Depression Anxiety Stress Scales 21. RESULTS: The number of memory complaints was not associated with memory or sustained attention performance but was associated with anxiety symptoms. The type of memory complaint was likewise not associated with memory or sustained attention performance. The complaints "recent change in ability to remember things" and "trouble remembering things from one second to the next" were associated with anxiety symptoms. CONCLUSION: Complaints about memory in otherwise healthy middle-aged adults do not reliably indicate memory or sustained attention performance. Rather, these complaints are more likely to be associated with heightened, but nevertheless subclinical, anxiety.

Novel pharmacological strategies to treat cognitive dysfunction in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and currently the 3rd largest cause of death in the world, with approximately 3.23 million deaths per year. Globally, the financial burden of COPD is approximately €82 billion per year and causes substantial morbidity and mortality. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and viral and bacterial-induced acute exacerbations (AECOPD). Recent clinical studies have shown that cognitive dysfunction is present in up to 60% of people with COPD, with impairments in executive function, memory, and attention, impacting on important outcomes such as quality of life, hospitalisation and survival. The high prevalence of cognitive dysfunction in COPD may also help explain the insufficient adherence to therapeutic plans and strategies, thus worsening disease progression in people with COPD. However, the mechanisms underlying the impaired neuropathology and cognition in COPD remain largely unknown. In this review, we propose that the observed pulmonary oxidative burden and inflammatory response of people with COPD 'spills over' into the systemic circulation, resulting in damage to the brain and leading to cognitive dysfunction. As such, drugs targeting the lungs and comorbidities concurrently represent an exciting and unique therapeutic opportunity to treat COPD and cognitive impairments, which may lead to the production of novel targets to prevent and reverse the debilitating and life-threatening effects of cognitive dysfunction in COPD.

Association of Stress with Risk of Dementia and Mild Cognitive Impairment: A Systematic Review and Meta-Analysis.

BACKGROUND: Although many studies have investigated the association between stress and risk of dementia, findings are inconsistent due to the variation in the measures used to assess stress. OBJECTIVE: We conducted a systematic review and meta-analysis to investigate the association between psychological stress (including neuroticism, stressful life events, and perceived stress) and the risk of incident dementia and mild cognitive impairment in adults. METHODS: PsycINFO, Embase, and MEDLINE were searched to October 2020 for eligible observational, prospective studies. Of the 1,607 studies screened, 26 (24 unique cohorts) were included in the qualitative analysis and 16 (15 unique cohorts) were included in the quantitative analysis. RESULTS: Across studies, higher perceived stress was significantly associated with an increased risk of mild cognitive impairment (Cases/Total N = 207/860: hazard ratio [HR] = 1.19, 95% confidence interval [CI] = 1.03-1.38) and all-cause dementia (Cases/Total N = 203/1,882: HR = 1.44, 95% CI = 1.07-1.95). Exposure to two or more stressful life events (versus none) was significantly associated with an increased risk of all-cause dementia (Cases/Total N = 3,354/11,597: HR = 1.72, 95% CI = 1.14-2.60), while one or more stressful life events was not. Higher neuroticism was significantly associated with an increased risk of Alzheimer's disease dementia (Cases/Total N = 497/4,771: HR = 1.07, 95% CI = 1.01-1.12), but not all-cause dementia. CONCLUSION: This review suggests that psychological stress in adulthood is associated with an increased risk of dementia. Further research is needed to clarify the mechanisms underlying these associations.

Supranutritional Sodium Selenate Supplementation Delivers Selenium to the Central Nervous System: Results from a Randomized Controlled Pilot Trial in Alzheimer's Disease.

Insufficient supply of selenium to antioxidant enzymes in the brain may contribute to Alzheimer's disease (AD) pathophysiology; therefore, oral supplementation may potentially slow neurodegeneration. We examined selenium and selenoproteins in serum and cerebrospinal fluid (CSF) from a dual-dose 24-week randomized controlled trial of sodium selenate in AD patients, to assess tolerability, and efficacy of selenate in modulating selenium concentration in the central nervous system (CNS). A pilot study of 40 AD cases was randomized to placebo, nutritional (0.32 mg sodium selenate, 3 times daily), or supranutritional (10 mg, 3 times daily) groups. We measured total selenium, selenoproteins, and inorganic selenium levels, in serum and CSF, and compared against cognitive outcomes. Supranutritional selenium supplementation was well tolerated and yielded a significant (p < 0.001) but variable (95% CI = 13.4-24.8 µg/L) increase in CSF selenium, distributed across selenoproteins and inorganic species. Reclassifying subjects as either responsive or non-responsive based on elevation in CSF selenium concentrations revealed that responsive group did not deteriorate in Mini-Mental Status Examination (MMSE) as non-responsive group (p = 0.03). Pooled analysis of all samples revealed that CSF selenium could predict change in MMSE performance (Spearman's rho = 0.403; p = 0.023). High-dose sodium selenate supplementation is well tolerated and can modulate CNS selenium concentration, although individual variation in selenium metabolism must be considered to optimize potential benefits in AD. The Vel002 study is listed on the Australian and New Zealand Clinical Trials Registry ( http://www.anzctr.org.au /), ID: ACTRN12611001200976.

Depression, fatigue and neurocognitive deficits in chronic hepatitis C.

Patients with chronic hepatitis C virus (HCV) infection experience a range of symptoms including depression, fatigue and neurocognitive deficits, impairing quality of life. Depression, in particular, may be reactive to increased psychosocial stress, and the physical symptoms of advanced HCV or associated comorbidities. However, even patients at an early stage of HCV infection, with minimal hepatic inflammation or comorbidities, report more depressive symptoms and fatigue than the general population. Similarly, specific neurocognitive deficits occur in early stage HCV infection and are independent of the presence of depression or encephalopathy. Therefore, intracerebral neurobiological changes associated with HCV may potentially explain these symptoms. These changes may arise from infiltration of the brain by peripherally induced cytokines, as well as direct neuropathic effects of HCV viral particles penetrating the blood-brain barrier. These phenomena parallel those reported in human immunodeficiency virus (HIV) infection. HCV-associated intracerebral changes include upregulated inflammatory responses, altered neurotransmitter levels, hormonal dysregulation, and release of neurotoxic substances. These may subsequently lead to abnormal neuronal conduction and function in areas of the brain governing affective responses, emotional processing, motivation, attention and concentration. Although direct-acting antiviral medications lead to high rates of HCV clearance, intracerebral changes may not be subsequently reversed and symptoms of depression, fatigue and neurocognitive deficits may persist. There is an ongoing role for multidisciplinary care and pharmacotherapy to manage these symptoms in HCV patients. Furthermore, there may be opportunities for future therapies to specifically target and ameliorate HCV-associated intracerebral changes.

Cerebrospinal Fluid Biomarkers are Differentially Related to Structural and Functional Changes in Dementia of the Alzheimer's Type.

The two cardinal pathologies of Alzheimer's disease (AD) develop according to distinct anatomical trajectories. Cerebral tau-related pathology first accumulates in the mesial temporal region, while amyloid-related pathology first appears in neocortex. The eventual distributions of these pathologies reflect their anatomical origins. An implication is that the cardinal pathologies might exert preferential effects on the structurofunctional brain changes observed in AD. We investigated this hypothesis in 39 patients with dementia of the Alzheimer's type. Interrelationships were analyzed between cerebrospinal fluid biomarkers of the cardinal pathologies, volumetric brain changes using magnetic resonance imaging, and brain metabolism using [18F]-FDG-PET. Amyloid-related pathology was preferentially associated with structurofunctional changes in the precuneus and lateral temporal regions. Tau-related pathology was not associated with changes in these regions. These findings support the hypothesis that tau- and amyloid-pathology exert differential effects on structurofunctional changes in the AD brain. These findings have implications for future therapeutic trials and hint at a more complex relationship between the cardinal pathologies and disruption of brain networks.

Cognitive clusters in first-episode psychosis: Overlap with healthy controls and relationship to concurrent and prospective symptoms and functioning.

OBJECTIVE: To identify cognitive subgroups (comprising neurocognition and social cognition domains) within first-episode psychosis (FEP) patients including a healthy control group for comparison. Predictive validity of cognitive clusters in relation to symptoms and functioning was also investigated. METHOD: A comprehensive cognitive battery was administered to 133 FEP participants and 46 healthy controls. Ward's method hierarchical agglomerative cluster analysis with k-means verification was used to determine clusters. Clusters were externally validated and 6-month predictive validity was also examined. RESULTS: Three distinct clusters were identified and were defined by degree of impairment rather than specific deficit profiles. Social-cognitive performance mirrored neurocognitive performance in each cluster. Cluster 1 was characterized by significant widespread cognitive impairments (1-2 SD below the mean) and solely comprised FEP participants (n = 24). Cluster 2 suggested moderately impaired cognitive functioning (within 0.5 SD below the mean), and comprised mostly FEP participants and 2 healthy controls (n = 73). Cluster 3 showed a pattern of cognitively intact performance across domains and comprised 37 FEP participants and 44 healthy controls (n = 81). Premorbid IQ, negative symptom severity, and functioning were significantly associated with cluster membership at baseline. At 6-month follow-up, cluster membership remained significantly associated with negative symptoms and functioning. CONCLUSIONS: The heterogeneity of cognition in FEP may be based on degree of impairment across both neurocognitive and social-cognitive domains. Cognitive clusters were associated with symptom and functional outcome, suggesting that measurement of cognition at entry to treatment may be useful for prognosis and treatment. (PsycINFO Database Record

Hand preference is selectively related to common and internal carotid arterial asymmetry.

This study documents relationships between handedness and carotid arterial asymmetries. The article is divided into two sections, considering first geometric (n = 195) and then haemodynamic (n = 228) asymmetries. In the geometric study, diameters, lengths, and angles of the common carotid arteries in left and right-handed participants were measured using computed tomography angiography scans. Resistance to blood flow was calculated according to Poiseuille's formula. In the haemodynamic study, peak systolic and end-diastolic velocity, vessel diameter, and volume flow rate of the common, internal, and external carotid arteries were measured in left and right-handed participants, using Doppler ultrasonography. The findings reveal for the first time that the extracranial arteries supplying the cerebral hemispheres are asymmetrical in a direction that increases blood flow to the hemisphere dominant for handedness. Significant handedness interactions were identified in arterial length, diameter, resistance to blood flow, velocity and flow volume rate (p < .001). Arterial resistance and volume flow rates significantly predicted hand preference and proficiency. Our findings reveal a vascular correlate of handedness, but causality cannot be determined from this study alone. These asymmetries appear to be independent of aortic arch anomalies, suggesting a top-down, possibly demand-driven, pattern of development.

Automatization of personal and impersonal discourse with narrative re-telling as a function of age.

When older adults retell an impersonal story, the resulting narratives are typically characterized by more prolixity and less coherence than those produced by younger adults. We aimed to determine whether this pattern is also observed when retelling a personal narrative. Younger and older participants told a personal story three consecutive times. With retelling, no evidence of increased coherence or fluency or reduction in hesitancy was observed for either age group. The nature of autobiographical narrative construction explains why such stories are not subject to automatization. A failure to automatize personal narratives is not, therefore, a symptom of aging.

A Phase IIa Randomized Control Trial of VEL015 (Sodium Selenate) in Mild-Moderate Alzheimer's Disease.

BACKGROUND: There is increasing interest in targeting hyperphosphorylated tau (h-tau) as a disease modifying approach for Alzheimer's disease (AD). Sodium selenate directly stimulates the activity of PP2A, the main enzyme responsible for h-tau dephosphorylation in the brain. OBJECTIVE: This study assessed the safety and tolerability of 24-week treatment with VEL015 (sodium selenate) in AD. Investigating the effects of VEL015 on cognitive, CSF, and neuroimaging biomarkers of AD were secondary, exploratory objectives. Data were used to identify biomarkers showing most promise for use in subsequent efficacy trials. METHODS: A 24-week, multicenter, Phase IIa, double-blinded randomized controlled trial. Forty patients aged ≥55 y with mild-moderate AD (MMSE 14-26) were randomized to supranutritional (VEL015 10 mg tds [n = 20]) and control (VEL015 320µg tds [n = 10] or placebo [n = 10]) groups. Patients were regularly monitored for safety, adverse events (AEs), and protocol compliance. Exploratory biomarkers included cognitive tests, neuroimaging (diffusion MR), and CSF (p-tau, t-tau, and Aß1-42). RESULTS: Thirty-six (90%; [supranutritional n = 18, control/placebo n = 18]) patients completed the trial. There were no differences in the incidence of specific AEs between groups. Only one secondary biomarker, diffusion MR measures, showed group differences, with less deterioration in the supranutritional group (p < 0.05). CONCLUSION: Treatment with VEL015 at doses up to 30 mg per day for 24 weeks was safe and well-tolerated in patients with AD. Diffusion MR measures appear to be the most sensitive biomarkers to assess disease progression over 24 weeks.

Differential Functional Connectivity Correlates of Cerebrospinal Fluid Biomarkers in Dementia of the Alzheimer's Type.

BACKGROUND: Alzheimer's disease (AD) is characterized by two cardinal pathologies, which have different topological distributions. The differential anatomical distributions of these pathologies raise the possibility that they exert differential effects on brain networks. OBJECTIVES: To investigate whether cerebrospinal fluid (CSF) biomarkers of the cardinal pathologies have differential relationships with functional connectivity networks in patients with dementia of the Alzheimer's type (DAT). METHODS: Thirty-nine participants underwent CSF sampling and resting-state functional magnetic resonance imaging. Functional connectivity networks were computed for each participant. CSF biomarker levels of p-tau and amyloid-ß (Aß) were regressed onto these networks to identify subnetworks associated with each biomarker. RESULTS: A subnetwork associated with tau-related pathology was identified with its hub in the right anterior entorhinal cortex. A separate subnetwork associated with Aß with its hub in the right dorsal anterior cingulate cortex was identified. CONCLUSION: These results demonstrate the differential effects of AD biomarkers on functional connectivity networks, supporting a possible division of labour between the cardinal pathologies.

Strategies for improving memory: a randomized trial of memory groups for older people, including those with mild cognitive impairment.

BACKGROUND: Governments are promoting the importance of maintaining cognitive health into older age to minimize risk of cognitive decline and dementia. Older people with amnestic mild cognitive impairment (aMCI) are particularly vulnerable to memory challenges in daily activities and are seeking ways to maintain independent living. OBJECTIVE: To evaluate the effectiveness of memory groups for improving memory strategies and memory ability of older people, especially those with aMCI. METHODS: 113 healthy older adults (HOA) and 106 adults with aMCI were randomized to a six-week memory group or a waitlist control condition. Outcome was evaluated through knowledge and use of memory strategies, memory ability (self-report and neuropsychological tests), and wellbeing. Assessments included a six-month follow-up. RESULTS: Using intention to treat analyses, there were intervention effects for HOA and aMCI groups in strategy knowledge (HOA: η2= 0.20; aMCI: η2= 0.06), strategy use (HOA: η2= 0.18; aMCI: η2= 0.08), and wellbeing (HOA: η2= 0.11; aMCI: η2= 0.05). There were also intervention effects in the HOA group, but not the aMCI group, in self-reported memory ability (η2= 0.06) and prospective memory tests (η2= 0.02). By six-month follow-up, gains were found on most HOA outcomes. In the aMCI group gains were found in strategy use, and by this stage, gains in prospective memory were also found. CONCLUSION: Memory groups can engage older people in techniques for maintaining cognitive health and improve memory performance, but more modest benefits are seen for older adults with aMCI.

MRI correlates of general intelligence in neurotypical adults.

There is growing interest in the neurobiological substrate of general intelligence. Psychometric estimates of general intelligence are reduced in a range of neurological disorders, leading to practical application as sensitive, but non-specific, markers of cerebral disorder. This study examined estimates of general intelligence in neurotypical adults using diffusion tensor imaging and resting-state functional connectivity analysis. General intelligence was related to white matter organisation across multiple brain regions, confirming previous work in older healthy adults. We also found that variation in general intelligence was related to a large functional sub-network involving all cortical lobes of the brain. These findings confirm that individual variance in general intelligence is related to diffusely represented brain networks.

Hippocampal 5-HT1A Receptor and Spatial Learning and Memory.

Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory.