Exposure to traumatic experiences during childhood and adolescence is a significant risk factor for the development of psychiatric disorders in adulthood. An estimated 50% of the worldwide incidence of depression and anxiety can be attributed to childhood maltreatment (Li et al., 2016). In addition, approximately one-third of psychotic experiences are attributable to a history of developmental trauma (McGrath et al., 2017). It is thought that long-lasting, trauma-induced adaptive changes in neurobiological function may lead to a predisposition towards pathophysiology (McCrory and Viding, 2015). However, the precise mechanisms through which developmental trauma exposure alters brain function on cellular and circuit levels remain poorly elucidated.

A systematic literature search and meta-analysis was performed to establish how dopaminergic functioning in adulthood is affected by developmental stress in rodents. Three databases, Medline®, Embase®, and PsycINFO®, were systematically searched initially on 2nd December 2023. Terms for three superordinate concepts (‘childhood’ terms, ‘trauma’ terms, and ‘dopamine’ terms) were combined. Cohen's d statistic was used for effect sizes. This protocol is pre-registered on PROSPERO® (ID: CRD42018106382).

A total of 104 studies met our inclusion criteria. Meta-analysis indicated that developmental stress exposure leads to complex and long-lasting effects in basal and post-amphetamine extracellular dopamine concentrations in the medial prefrontal cortex, amygdala, and nucleus accumbens. In addition, there is a significant downregulation of D1 receptors and upregulation of D2 receptors in prefrontal and striatal regions involved in threat and reward processing. Effect sizes ranged from 0.36 to 1.55.

These findings strongly suggest that dopaminergic dysfunction is a mechanistic link between developmental trauma and vulnerability towards mental illness in adulthood.

Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations.

In 410 male and female participants aged 17–35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites.

Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake.

Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.

White matter hyperintensity (WMH) volume is a neuroimaging marker of lesion load related to small vessel disease that has been associated with cognitive aging and Alzheimer’s disease (AD) risk.

The present study sought to examine whether regional WMH volume mediates the relationship between APOE ε4 status, a strong genetic risk factor for AD, and cognition and if this association is moderated by age group differences within a sample of 187 healthy older adults (APOE ε4 status [carrier/non-carrier] = 56/131).

After we controlled for sex, education, and vascular risk factors, ANCOVA analyses revealed significant age group by APOE ε4 status interactions for right parietal and left temporal WMH volumes. Within the young-old group (50-69 years), ε4 carriers had greater right parietal and left temporal WMH volumes than non-carriers. However, in the old-old group (70-89 years), right parietal and left temporal WMH volumes were comparable across APOE ε4 groups. Further, within ε4 non-carriers, old-old adults had greater right parietal and left temporal WMH volumes than young-old adults, but there were no significant differences across age groups in ε4 carriers. Follow-up moderated mediation analyses revealed that, in the young-old, but not the old-old group, there were significant indirect effects of ε4 status on memory and executive functions through left temporal WMH volume.

These findings suggest that, among healthy young-old adults, increased left temporal WMH volume, in the context of the ε4 allele, may represent an early marker of cognitive aging with the potential to lead to greater risk for AD.

Cognitive training is a non-pharmacological intervention aimed at improving cognitive function across a single or multiple domains. Although the underlying mechanisms of cognitive training and transfer effects are not well-characterized, cognitive training has been thought to facilitate neural plasticity to enhance cognitive performance. Indeed, the Scaffolding Theory of Aging and Cognition (STAC) proposes that cognitive training may enhance the ability to engage in compensatory scaffolding to meet task demands and maintain cognitive performance. We therefore evaluated the effects of cognitive training on working memory performance in older adults without dementia. This study will help begin to elucidate non-pharmacological intervention effects on compensatory scaffolding in older adults.

48 participants were recruited for a Phase III randomized clinical trial (Augmenting Cognitive Training in Older Adults [ACT]; NIH R01AG054077) conducted at the University of Florida and University of Arizona. Participants across sites were randomly assigned to complete cognitive training (n=25) or an education training control condition (n=23). Cognitive training and the education training control condition were each completed during 60 sessions over 12 weeks for 40 hours total. The education training control condition involved viewing educational videos produced by the National Geographic Channel. Cognitive training was completed using the Posit Science Brain HQ training program, which included 8 cognitive training paradigms targeting attention/processing speed and working memory. All participants also completed demographic questionnaires, cognitive testing, and an fMRI 2-back task at baseline and at 12-weeks following cognitive training.

Repeated measures analysis of covariance (ANCOVA), adjusted for training adherence, transcranial direct current stimulation (tDCS) condition, age, sex, years of education, and Wechsler Test of Adult Reading (WTAR) raw score, revealed a significant 2-back by training group interaction (F[1,40]=6.201, p=.017, η2=.134). Examination of simple main effects revealed baseline differences in 2-back performance (F[1,40]=.568, p=.455, η2=.014). After controlling for baseline performance, training group differences in 2-back performance was no longer statistically significant (F[1,40]=1.382, p=.247, η2=.034).

After adjusting for baseline performance differences, there were no significant training group differences in 2-back performance, suggesting that the randomization was not sufficient to ensure adequate distribution of participants across groups. Results may indicate that cognitive training alone is not sufficient for significant improvement in working memory performance on a near transfer task. Additional improvement may occur with the next phase of this clinical trial, such that tDCS augments the effects of cognitive training and results in enhanced compensatory scaffolding even within this high performing cohort. Limitations of the study include a highly educated sample with higher literacy levels and the small sample size was not powered for transfer effects analysis. Future analyses will include evaluation of the combined intervention effects of a cognitive training and tDCS on nback performance in a larger sample of older adults without dementia.

Cognitive training using a visual speed-of-processing task, called the Useful Field of View (UFOV) task, reduced dementia risk and reduced decline in activities of daily living at a 10-year follow-up in older adults. However, there is variability in the level of cognitive gains after cognitive training across studies. One potential explanation for this variability could be moderating factors. Prior studies suggest variables moderating cognitive training gains share features of the training task. Learning trials of the Hopkins Verbal Learning Test-Revised (HVLT-R) and Brief Visuospatial Memory Test-Revised (BVMT-R) recruit similar cognitive abilities and have overlapping neural correlates with the UFOV task and speed-ofprocessing/working memory tasks and therefore could serve as potential moderators. Exploring moderating factors of cognitive training gains may boost the efficacy of interventions, improve rigor in the cognitive training literature, and eventually help provide tailored treatment recommendations. This study explored the association between the HVLT-R and BVMT-R learning and the UFOV task, and assessed the moderation of HVLT-R and BVMT-R learning on UFOV improvement after a 3-month speed-ofprocessing/attention and working memory cognitive training intervention in cognitively healthy older adults.

75 healthy older adults (M age = 71.11, SD = 4.61) were recruited as part of a larger clinical trial through the Universities of Florida and Arizona. Participants were randomized into a cognitive training (n=36) or education control (n=39) group and underwent a 40-hour, 12-week intervention. Cognitive training intervention consisted of practicing 4 attention/speed-of-processing (including the UFOV task) and 4 working memory tasks. Education control intervention consisted of watching 40-minute educational videos. The HVLT-R and BVMT-R were administered at the pre-intervention timepoint as part of a larger neurocognitive battery. The learning ratio was calculated as: trial 3 total - trial 1 total/12 - trial 1 total. UFOV performance was measured at pre- and post-intervention time points via the POSIT Brain HQ Double Decision Assessment. Multiple linear regressions predicted baseline Double Decision performance from HVLT-R and BVMT-R learning ratios controlling for study site, age, sex, and education. A repeated measures moderation analysis assessed the moderation of HVLT-R and BVMT-R learning ratio on Double Decision change from pre- to post-intervention for cognitive training and education control groups.

Baseline Double Decision performance significantly associated with BVMT-R learning ratio (β=-.303, p=.008), but not HVLT-R learning ratio (β=-.142, p=.238). BVMT-R learning ratio moderated gains in Double Decision performance (p<.01); for each unit increase in BVMT-R learning ratio, there was a .6173 unit decrease in training gains. The HVLT-R learning ratio did not moderate gains in Double Decision performance (p>.05). There were no significant moderations in the education control group.

Better visuospatial learning was associated with faster Double Decision performance at baseline. Those with poorer visuospatial learning improved most on the Double Decision task after training, suggesting that healthy older adults who perform below expectations may show the greatest training gains. Future cognitive training research studying visual speed-of-processing interventions should account for differing levels of visuospatial learning at baseline, as this could impact the magnitude of training outcomes.

Aging is associated with disruptions in functional connectivity within the default mode (DMN), frontoparietal control (FPCN), and cingulo-opercular (CON) resting-state networks. Greater within-network connectivity predicts better cognitive performance in older adults. Therefore, strengthening network connectivity, through targeted intervention strategies, may help prevent age-related cognitive decline or progression to dementia. Small studies have demonstrated synergistic effects of combining transcranial direct current stimulation (tDCS) and cognitive training (CT) on strengthening network connectivity; however, this association has yet to be rigorously tested on a large scale. The current study leverages longitudinal data from the first-ever Phase III clinical trial for tDCS to examine the efficacy of an adjunctive tDCS and CT intervention on modulating network connectivity in older adults.

This sample included 209 older adults (mean age = 71.6) from the Augmenting Cognitive Training in Older Adults multisite trial. Participants completed 40 hours of CT over 12 weeks, which included 8 attention, processing speed, and working memory tasks. Participants were randomized into active or sham stimulation groups, and tDCS was administered during CT daily for two weeks then weekly for 10 weeks. For both stimulation groups, two electrodes in saline-soaked 5x7 cm2 sponges were placed at F3 (cathode) and F4 (anode) using the 10-20 measurement system. The active group received 2mA of current for 20 minutes. The sham group received 2mA for 30 seconds, then no current for the remaining 20 minutes.

Participants underwent resting-state fMRI at baseline and post-intervention. CONN toolbox was used to preprocess imaging data and conduct region of interest (ROI-ROI) connectivity analyses. The Artifact Detection Toolbox, using intermediate settings, identified outlier volumes. Two participants were excluded for having greater than 50% of volumes flagged as outliers. ROI-ROI analyses modeled the interaction between tDCS group (active versus sham) and occasion (baseline connectivity versus postintervention connectivity) for the DMN, FPCN, and CON controlling for age, sex, education, site, and adherence.

Compared to sham, the active group demonstrated ROI-ROI increases in functional connectivity within the DMN following intervention (left temporal to right temporal [T(202) = 2.78, pFDR < 0.05] and left temporal to right dorsal medial prefrontal cortex [T(202) = 2.74, pFDR < 0.05]. In contrast, compared to sham, the active group demonstrated ROI-ROI decreases in functional connectivity within the FPCN following intervention (left dorsal prefrontal cortex to left temporal [T(202) = -2.96, pFDR < 0.05] and left dorsal prefrontal cortex to left lateral prefrontal cortex [T(202) = -2.77, pFDR < 0.05]). There were no significant interactions detected for CON regions.

These findings (a) demonstrate the feasibility of modulating network connectivity using tDCS and CT and (b) provide important information regarding the pattern of connectivity changes occurring at these intervention parameters in older adults. Importantly, the active stimulation group showed increases in connectivity within the DMN (a network particularly vulnerable to aging and implicated in Alzheimer’s disease) but decreases in connectivity between left frontal and temporal FPCN regions. Future analyses from this trial will evaluate the association between these changes in connectivity and cognitive performance post-intervention and at a one-year timepoint.

The National Institutes of Health-Toolbox cognition battery (NIH-TCB) is widely used in cognitive aging studies and includes measures in cognitive domains evaluated for dimensional structure and psychometric properties in prior research. The present study addresses a current literature gap by demonstrating how NIH-TCB integrates into a battery of traditional clinical neuropsychological measures. The dimensional structure of NIH-TCB measures along with conventional neuropsychological tests is assessed in healthy older adults.

Baseline cognitive data were obtained from 327 older adults. The following measures were collected: NIH-Toolbox cognitive battery, Controlled Oral Word Association (COWA) letter and animals tests, Wechsler Test of Adult Reading (WTAR), Stroop Color-Word Interference Test, Paced Auditory Serial Addition Test (PASAT), Brief Visuospatial Memory Test (BVMT), Letter-Number Sequencing (LNS), Hopkins Verbal Learning Test (HVLT), Trail Making Test A&B, Digit Span. Hmisc, psych, and GPARotation packages for R were used to conduct exploratory factor analyses (EFA). A 5-factor solution was conducted followed by a 6-factor solution. Promax rotation was used for both EFA models.

The 6-factor EFA solution is reported here. Results indicated the following 6 factors: working memory (Digit Span forward, backward, and sequencing, PASAT trials 1 and 2, NIH-Toolbox List Sorting, LNS), speed/executive function (Stroop color naming, word reading, and color-word interference, NIH-Toolbox Flanker, Dimensional Change, and Pattern Comparison, Trail Making Test A&B), verbal fluency (COWA letters F-A-S), crystallized intelligence (WTAR, NIH-Toolbox Oral Recognition and Picture Vocabulary), visual memory (BVMT immediate and delayed), and verbal memory (HVLT immediate and delayed. COWA animals and NIH-Toolbox Picture Sequencing did not adequately load onto any EFA factor and were excluded from the subsequent CFA.

Findings indicate that in a sample of healthy older adults, these collected measures and those obtained through the NIH-Toolbox battery represent 6 domains of cognitive function. Results suggest that in this sample, picture sequencing and COWA animals did not load adequately onto the factors created from the rest of the measures collected. These findings should assist in interpreting future research using combined NIH-TCB and neuropsychological batteries to assess cognition in healthy older adults.

Nonpathological aging has been linked to decline in both verbal and visuospatial memory abilities in older adults. Disruptions in resting-state functional connectivity within well-characterized, higherorder cognitive brain networks have also been coupled with poorer memory functioning in healthy older adults and in older adults with dementia. However, there is a paucity of research on the association between higherorder functional connectivity and verbal and visuospatial memory performance in the older adult population. The current study examines the association between resting-state functional connectivity within the cingulo-opercular network (CON), frontoparietal control network (FPCN), and default mode network (DMN) and verbal and visuospatial learning and memory in a large sample of healthy older adults. We hypothesized that greater within-network CON and FPCN functional connectivity would be associated with better immediate verbal and visuospatial memory recall. Additionally, we predicted that within-network DMN functional connectivity would be associated with improvements in delayed verbal and visuospatial memory recall. This study helps to glean insight into whether within-network CON, FPCN, or DMN functional connectivity is associated with verbal and visuospatial memory abilities in later life.

330 healthy older adults between 65 and 89 years old (mean age = 71.6 ± 5.2) were recruited at the University of Florida (n = 222) and the University of Arizona (n = 108). Participants underwent resting-state fMRI and completed verbal memory (Hopkins Verbal Learning Test - Revised [HVLT-R]) and visuospatial memory (Brief Visuospatial Memory Test - Revised [BVMT-R]) measures. Immediate (total) and delayed recall scores on the HVLT-R and BVMT-R were calculated using each test manual’s scoring criteria. Learning ratios on the HVLT-R and BVMT-R were quantified by dividing the number of stimuli (verbal or visuospatial) learned between the first and third trials by the number of stimuli not recalled after the first learning trial. CONN Toolbox was used to extract average within-network connectivity values for CON, FPCN, and DMN. Hierarchical regressions were conducted, controlling for sex, race, ethnicity, years of education, number of invalid scans, and scanner site.

Greater CON connectivity was significantly associated with better HVLT-R immediate (total) recall (ß = 0.16, p = 0.01), HVLT-R learning ratio (ß = 0.16, p = 0.01), BVMT-R immediate (total) recall (ß = 0.14, p = 0.02), and BVMT-R delayed recall performance (ß = 0.15, p = 0.01). Greater FPCN connectivity was associated with better BVMT-R learning ratio (ß = 0.13, p = 0.04). HVLT-R delayed recall performance was not associated with connectivity in any network, and DMN connectivity was not significantly related to any measure.

Connectivity within CON demonstrated a robust relationship with different components of memory function as well across verbal and visuospatial domains. In contrast, FPCN only evidenced a relationship with visuospatial learning, and DMN was not significantly associated with memory measures. These data suggest that CON may be a valuable target in longitudinal studies of age-related memory changes, but also a possible target in future non-invasive interventions to attenuate memory decline in older adults.

Pain, depression, anxiety, and psychosis are common non-cognitive symptoms of dementia. They are often underdiagnosed and can cause significant distress and carer strain. Numerous standardised assessment tools (SATs) exist and are recommended for the assessment of non-cognitive symptoms of dementia. Anecdotal evidence suggests that SATs are used rarely and inconsistently. This study aims to explore which SATs to detect non-cognitive symptoms of dementia are recommended in local guidelines and used in practice across different organisations. Secondary aims were to identify barriers and facilitators to using these tools.

This service evaluation is cross-sectional in design. A questionnaire was developed and distributed to clinicians working with patients with advanced dementia in any setting, across four geographical locations (Leeds, Bradford, Hull, and Cambridge). Quantitative data were analysed descriptively, and qualitative data from free-text comments were interpreted using thematic analysis.

135 professionals from a range of backgrounds and clinical settings completed the survey. Respondents indicated that SATs for non-cognitive symptoms in dementia were rarely used or recommended. Respondents were unaware of the existence of most SATs listed. 80% respondents felt that SATs were a useful adjunct to a structured clinical assessment. The most recommended tool was the Abbey Pain Scale, with 41 respondents indicating its recommendation by their Trust. Perceived facilitators to using SATs include education and training, reliable IT systems and accessibility. Barriers include lack of time and training.

Numerous SATs are available for use in dementia, but they are rarely recommended in local policy or used in practice. There appears to be a lack of consensus on which, if any, are superior diagnostic tools, and on how or when they should be applied.

To study the clinical profile and outcomes of patients with paraproteinemic neuropathy (PPN) and to explore the utility of nerve conduction studies (NCSs) to differentiate between the demyelinating subtypes.

We did a retrospective analysis of patients diagnosed with PPN between January 2010 and December 2019 in an inpatient setting. The study population consisted of patients above 16 years of age presenting with clinical features suggestive of chronic peripheral neuropathy and on evaluation was found to have PPN.

A total of 74 patients were identified. The patients were predominantly in the 6th decade, and the majority were males. The subtypes of PPN were monoclonal gammopathy of undetermined significance (MGUS) (45.9%), POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes) (24.3%), solitary plasmacytoma (17.6%), multiple myeloma (8.1%), and AL amyloidosis (4.1%). There are specific features on NCS which can help in identifying POEMS syndrome and IgM MGUS. The majority of patients with PPN tend to stabilize or improve with treatment; however, many have a severe residual disability. New terminology and classification of these entities as ‘monoclonal gammopathies of neurological significance’ can aid in early diagnosis and the development of effective treatment, to prevent residual disability.

PPN has a heterogeneous spectrum of clinical, biochemical, and electrophysiological features. NCS can help distinguish POEMS syndrome and IgM MGUS from other demyelinating subtypes.

Tuberous sclerosis complex (TSC) is a rare genetic disorder that commonly leads to drug-resistant epilepsy in affected patients. This study aimed to determine whether the underlying genetic mutation (TSC1 vs. TSC2) predicts seizure outcomes following surgical treatments for epilepsy.

We retrospectively assessed TSC patients using the TSC Natural History Database core registry. Data review focused on outcomes in patients treated with surgical resection or vagus nerve stimulation.

A total of 42 patients with a TSC1 mutation, and 145 patients with a TSC2 mutation, were identified. We observed a distinct clinical phenotype: children with TSC2 mutations tended to be diagnosed with TSC at a younger age than those with a TSC1 mutation (p < 0.001), were more likely to have infantile spasms (p < 0.001), and to get to surgery at a later age (p = 0.003). Among this TSC2 cohort, seizure control following resective epilepsy surgery was achieved in less than half (47%) the study sample. In contrast, patients with TSC1 mutations tended to have more favorable postsurgical outcomes; seizure control was achieved in 66% of this group.

TSC2 mutations result in a more severe epilepsy phenotype that is also less responsive to resective surgery. It is important to consider this distinct clinical disposition when counseling families preoperatively with respect to seizure freedom. Larger samples are required to better characterize the independent effects of genetic mutation, infantile spasms, and duration of epilepsy as they relate to seizure control following resective or neuromodulatory epilepsy surgery.