Effect of estradiol on cognition in men undergoing androgen deprivation therapy: A randomized placebo-controlled trial.

OBJECTIVE: Roles for estradiol in modulating cognition in men remain uncertain. We assessed the isolated effects of estradiol on cognition in men in the absence of testosterone. DESIGN: Randomized trial of transdermal estradiol 0.9 mg daily, or matched placebo, for 6 months, hypothesizing that estradiol would improve verbal learning, verbal memory, and spatial problem solving over time. PATIENTS: Men receiving androgen deprivation therapy (ADT) for prostate cancer. MEASUREMENTS: Cognition was assessed by a tablet-based cognitive battery (Cogstate) at baseline, Month 1, Month 3, and Month 6. Anxiety and depression symptoms were assessed using the Hospital Anxiety and Depression Scale. RESULTS: Seventy-eight participants were randomized. Baseline mean scores were 21.0 (standard deviation [SD] 4.1) for the International Shopping List test (ISL), assessing verbal learning and memory (higher scores better), and 60.4 (SD 19.5) for the Groton Maze Learning test (GML), assessing spatial problem solving (lower scores better). There was no significant difference in performance over time for the estradiol group versus the placebo group for the ISL, mean adjusted difference (MAD) 0.7 (95% confidence interval [CI] -1.2 to 2.5), p = .36, or the GML, MAD -3.2 (95% CI -12.0 to 5.6), p = 0.53. There was no significant difference between groups over time in performance in any other cognitive domain, or on depression or anxiety scores. CONCLUSIONS: We found no major effects of estradiol on cognition in men with castrate testosterone concentrations. Although the cognitive effects of ADT are debated, this study suggests that any such effects are unlikely to be prevented by the administration of estradiol.

Contribution of autobiographic memory impairment to subjective memory complaints in focal epilepsy.

"My memory is terrible!" is a common refrain among people with epilepsy, but such complaints are not reliably linked to poor performances on standard tests of memory. Negative affect like depression and anxiety are the most robust predictor of these complaints; however, neither do they entirely account for the phenomenon. The contribution of autobiographic memory impairment to subjective memory complaints in focal epilepsy has not been well-explored despite autobiographic memory impairments being common in patients with epilepsy, and the face validity of relating day-to-day memory failings to such a personally relevant form of memory. The current study sought to clarify whether autobiographic memory dysfunction contributes to subjective complaints in epilepsy, above and beyond negative affect, objective memory impairment, and epileptological factors in a large sample of patients with drug-resistant focal epilepsy relative to healthy controls (N = 135). Patients were stratified into groups with mesial temporal (MT; n = 40) versus nonmesial temporal (NMT; n = 46) foci. Compared to controls (n = 46), both patient groups reported more bitter subjective memory complaints (p < 0.001, large effect size), demonstrated poorer episodic (p = 0.001, large effect size) and semantic autobiographical recall (p = 0.004, medium effect size), and had higher levels of depressive symptomatology (p = 0.011, medium effect size), and trait neuroticism (p = 0.015, medium effect size). Contrary to expectations, multiple regression analyses revealed that autobiographic memory function was not an independent predictor of subjective memory complaints in either group with epilepsy. In people with epilepsy with MT foci, objective verbal memory dysfunction, neuroticism, and female gender predicted memory complaints (R2 = 0.70, p = 0.015), whereas only neuroticism predicted memory complaints in people with epilepsy with NMT foci (R2 = 0.21, p = 0.001). Although patients' poor recall of their autobiographical memories did not contribute to their concerns about their day-to-day memory function, the findings indicate that the location of the epileptogenic focus can provide clues as to the underlying contributors to subjective memory complaints in focal epilepsy. Important clinical implications to stem from these findings include the need for clinicians to adopt a patient-tailored, multifactorial lens when managing memory complaints in people with epilepsy, taking into account both psychological and cognitive factors.

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.

Bilateral volume reduction in posterior hippocampus in psychosis of epilepsy.

OBJECTIVE: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research. METHODS: In this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). RESULTS: Compared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups. CONCLUSION: Posterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.

Systematic review of structural and functional brain alterations in psychosis of epilepsy.

This systematic review critically assesses structural and functional neuroimaging studies of psychosis of epilepsy (POE). We integrate findings from 18 studies of adults with POE to examine the prevailing view that there is a specific relationship between temporal lobe epilepsy (TLE) and POE, and that mesial temporal lobe pathology is a biomarker for POE. Our results show: (1) conflicting evidence of volumetric change in the hippocampus and amygdala; (2) distributed structural pathology beyond the mesial temporal lobe; and (3) changes in frontotemporal functional network activation. These results provide strong evidence for a revised conceptualisation of POE as disorder of brain networks, and highlight that abnormalities in mesial temporal structures alone are unlikely to account for its neuropathogenesis. Understanding POE as a disease of brain networks has important implications for neuroimaging research and clinical practice. Specifically, we suggest that future neuroimaging studies of POE target structural and functional networks, and that practitioners are vigilant for psychotic symptoms in all epilepsies, not just TLE.

Altered self-identity and autobiographical memory in epilepsy.

OBJECTIVE: Research suggests that individuals with chronic epilepsy display differences in their self-identity. The mechanisms by which self-identity is altered, however, are not well understood. Neural networks supporting autobiographical memory retrieval in the mesial temporal (MT) lobe are thought to be fundamental to self-identity processes. Thus, we examined differences in self-identity and autobiographical memory in patients with either MT or non-mesial temporal (NMT) foci with early or late age of habitual seizure onset. METHODS: Participants included 102 adults: 51 healthy individuals and 51 patients with drug-resistant focal seizures (19 MT, 32 NMT). We used the Ego Identity Process Questionnaire to profile the identity development of participants, and examined how this related to memory function assessed using the Autobiographical Memory Test. RESULTS: Patients and controls had strikingly different self-identity profiles, with early onset MT patients showing the least identity development compared to controls and other patient groups. In contrast, late-onset NMT patients showed the highest level of identity development of the patient groups and closely resembled healthy controls (p < 0.05 for all comparisons). For all MT patients, poor autobiographical memory retrieval was correlated with altered self-identity (p < 0.001). No associations between autobiographical memory and self-identity were evident in the NMT group. SIGNIFICANCE: Self-identity in epilepsy may be modulated by the extent to which seizure foci impinge on the autobiographical memory network and the timing of seizure onset. Early disruption to MT regions of the autobiographical memory network may constitute a neurocognitive mechanism by which self-identity is altered in chronic focal epilepsy.

The effect of estradiol add-back: a longitudinal MRI study in prostate cancer patients.

We investigated the effect of estradiol add-back therapy (EAT) on brain activation related to cognitive function and affect in addition to putative changes in gray and white matter volume in testosterone depleted participants with prostate cancer. We conducted a randomized controlled, double-blinded trial in which 40 patients received 0.9 mg of transdermal estradiol per day for 6 months or matched placebo. Anatomical MRI and three functional MRI (fMRI) scans were obtained for the emotion recognition task, verbal memory task, and visuospatial memory task. Activation in corresponding cognitive and affective brain networks was demonstrated for all tasks. Longitudinally, there was no difference in brain activation, reaction time, or accuracy in response to the fMRI tasks between the EAT group and placebo group at 6 months. In addition, there was no detectable change in whole-brain gray or white matter volume or in hippocampal volume between the two groups after 6 months. This study supports earlier findings that EAT does not improve verbal memory or affect and has no immediate effect on hippocampal volume in testosterone depleted patients with prostate cancer.

Neuropsychological function in psychosis of epilepsy.

OBJECTIVE: The neuropsychological profile of patients with psychosis of epilepsy (POE) has received limited research attention. Recent neuroimaging work in POE has identified structural network pathology in the default mode network and the cognitive control network. This study examined the neuropsychological profile of POE focusing on cognitive domains subserved by these networks. METHODS: Twelve consecutive patients with a diagnosis of POE were prospectively recruited from the Comprehensive Epilepsy Programmes at The Royal Melbourne, Austin and St Vincent's Hospitals, Melbourne, Australia between January 2015 and February 2017. They were compared to 12 matched patients with epilepsy but no psychosis and 42 healthy controls on standardised neuropsychological tests of memory and executive functioning in a case-control design. RESULTS: Mean scores across all cognitive tasks showed a graded pattern of impairment, with the POE group showing the poorest performance, followed by the epilepsy without psychosis and the healthy control groups. This was associated with significant group-level differences on measures of working memory (p = < 0.01); immediate (p = < 0.01) and delayed verbal recall (p = < 0.01); visual memory (p < 0.001); and verbal fluency (p = 0.02). In particular, patients with POE performed significantly worse than the healthy control group on measures of both cognitive control (p = .005) and memory (p < .001), whereas the epilepsy without psychosis group showed only memory difficulties (delayed verbal recall) compared to healthy controls (p = .001). CONCLUSION: People with POE show reduced performance in neuropsychological functions supported by the default mode and cognitive control networks, when compared to both healthy participants and people with epilepsy without psychosis.

Increased cortical thickness in nodes of the cognitive control and default mode networks in psychosis of epilepsy.

OBJECTIVE: To explore the cortical morphological associations of the psychoses of epilepsy. METHODS: Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC; n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10). RESULTS: POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network; (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall. SIGNIFICANCE: The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset.