Cognitive performance in functional seizures compared with epilepsy and healthy controls: a systematic review and meta analysis.

BACKGROUND: Cognition is a core component of functional seizures, but the literature on cognition in this disorder has been heterogeneous, with no clear unifying profile emerging from individual studies. The aim of this study was to do a systematic review and meta-analysis of cognitive performance in adults with functional seizures compared with epilepsy (including left temporal lobe epilepsy) and compared with healthy non-seizure cohorts. METHODS: In this systematic review and meta-analysis, starting Feb 6, 2023, replicated and updated on Oct 31, 2023, a medical librarian searched MEDLINE, Embase, PsycINFO, and Web of Science. Inclusion criteria were full reports documenting raw or standardised cognitive test data in adults with functional seizures compared with adults with epilepsy, prospectively recruited healthy comparisons, or published norms. Grey literature was retained and there were no language or date restrictions. We excluded studies only reporting on mixed functional seizures and epilepsy, or mixed functional neurological samples, with no pure functional seizures group. Risk of bias was evaluated using a modified version of the Newcastle-Ottawa Scale. People with lived experiences were not involved in the design or execution of this study. This study is registered as CRD42023392385 in PROSPERO. FINDINGS: Of 3834 records initially identified, 84 articles were retained, including 8654 participants (functional seizures 4193, epilepsy 3638, and healthy comparisons 823). Mean age was 36 years (SD 12) for functional seizures, 36 years (12) for epilepsy, and 34 years (10) for healthy comparisons, and the proportion of women per group was 72% (range 18-100) for functional seizures, 59% (range 15-100) for epilepsy, and 69% (range 34-100) for healthy comparisons. Data on race or ethnicity were rarely reported in the individual studies. Risk of bias was moderate. Cognitive performance was better in people with functional seizures than those with epilepsy (Hedges' g=0·17 [95% CI 0·10-0·25)], p<0·0001), with moderate-to-high heterogeneity (Q[56]=128·91, p=0·0001, I2=57%). The functional seizures group performed better than the epilepsy group on global cognition and intelligence quotient (g=0·15 [0·02-0·28], p=0·022) and language (g=0·28 [0·14-0·43], p=0·0001), but not other cognitive domains. A larger effect was noted in language tests when comparing functional seizures with left temporal lobe epilepsy (k=5; g=0·51 [0·10 to 0·91], p=0·015). The functional seizures group underperformed relative to healthy comparisons (g=-0·61 [-0·78 to -0·44], p<0·0001), with significant differences in all cognitive domains. Meta regressions examining effects of multiple covariates on global cognition were not significant. INTERPRETATION: Patients with functional seizures have widespread cognitive impairments that are likely to be clinically meaningful on the basis of moderate effect sizes in multiple domains. These deficits might be slightly less severe than those seen in many patients with epilepsy but nevertheless argue for consideration of clinical assessment and treatment. FUNDING: Department of Veterans Affairs, Veterans Health Administration.

Digital Methods of Delivering Education and Training in Neuropsychology.

OBJECTIVE: High quality and accessible education is crucial to secure the future of neuropsychology. Recent and ongoing advancements include the creation of a taxonomy of education and training, progress in delineating relevant competencies, and an update to the Houston Conference Guidelines. Meanwhile, there is also potential for growth in digital methods of delivering education such as podcasts, webinars, and social media platforms. This paper aims to review the evidence for these three methods and to provide recommendations for implementing them across the continuum of training in neuropsychology, from graduate school through postdoctoral fellowship and continuing education. METHOD: We reviewed the literature on podcasts, webinars, and social media platforms as educational tools that may be applied to improve learning of brain-behavior concepts and clinical skills. Specifically, we (a) introduce and describe each method, (b) discuss benefits and drawbacks, (c) review the literature on satisfaction and learning outcomes, and (d) provide suggestions for implementation in neuropsychology training programs. RESULTS: Podcasts and webinars have strong evidence for satisfaction and moderate support for improving learning outcomes, with the learning outcome literature suggesting equivalency between podcasts/webinars and traditional methods of education. Social media platforms are associated with high satisfaction, but learning outcome data are scarce. CONCLUSIONS: Evidence for podcasts and webinars is sufficient to support implementation into neuropsychology education, whereas social media platforms should be used more cautiously. We provide recommendations of select instances in which trainees and educators can use these methods to improve education in neuropsychology.

Diverse experiences and approaches to tele neuropsychology: Commentary and reflections over the past year of COVID-19.

Objectives: In response to the coronavirus disease 2019 (COVID-19) pandemic, neuropsychologists rapidly adopted teleneuropsychology (TeleNP) services to ensure continued clinical care. Prior to COVID-19, TeleNP was not widely used nor was it included in the majority of traditional practice or training models across graduate, internship, and postdoctoral programs. Out of necessity, the pandemic was a catalyst that promoted greater adoption of TeleNP services. In response, neuropsychological guidelines for modified assessments were developed and further empirical studies have been published. Numerous surveys in response to service delivery changes during COVID-19 now exist, but what follows is a commentary based on neuropsychologists' experiences with adapting clinical practice to TeleNP. Methods: Co-authors represent settings across academic medical centers, Veterans Affairs hospitals, and private practices that serve multiculturally diverse pediatric, adult, and geriatric populations in the United States. Results: The perspectives within this commentary aim to highlight the growth of TeleNP and highlight lessons learned from implementation across practice settings. Conclusions: Our goal is to help foster the development of further empirical studies through candid discussion of various TeleNP experiences and approaches. Through this reflective process, TeleNP presents both opportunities and challenges but it ultimately has potential to reduce healthcare disparities and enhance patient care.

White matter integrity and functional predictors of response to repetitive transcranial magnetic stimulation for posttraumatic stress disorder and major depression.

BACKGROUND: Recent evidence suggests that therapeutic repetitive transcranial magnetic stimulation (TMS) is an effective treatment for pharmacoresistant posttraumatic stress disorder (PTSD) and comorbid major depressive disorder (MDD). We recently demonstrated that response to 5 Hz TMS administered to the dorsolateral prefrontal cortex was predicted by functional connectivity of the medial prefrontal (MPFC) and subgenual anterior cingulate cortex (sgACC). This functionally-defined circuit is a novel target for treatment optimization research, however, our limited knowledge of the structural pathways that underlie this functional predisposition is a barrier to target engagement research. METHODS: To investigate underlying structural elements of our previous functional connectivity findings, we submitted pre-TMS diffusion-weighted imaging data from 20 patients with PTSD and MDD to anatomically constrained tract-based probabilistic tractography (FreeSurfer's TRActs Constrained by UnderLying Anatomy). Averaged pathway fractional anisotropy (FA) was extracted from four frontal white matter tracts: the forceps minor, cingulum, anterior thalamic radiations (ATRs), and uncinate fasciculi. Tract FA statistics were treated as explanatory variables in backward regressions testing the relationship between tract integrity and functional connectivity coefficients from MPFC and sgACC predictors of symptom improvement after TMS. RESULTS: FA in the ATRs was consistently associated with symptom improvement in PTSD and MDD (Bonferroni-corrected p < .05). CONCLUSION: We found that structural characteristics of the ATR account for significant variance in individual-level functional predictors of post-TMS improvement. TMS optimization studies should target this circuit either in stand-alone or successive TMS stimulation protocols.

Pomegranate supplementation improves cognitive and functional recovery following ischemic stroke: A randomized trial.

Objectives: We tested whether supplementing with pomegranate polyphenols can enhance cognitive/functional recovery after stroke. Methods: In this parallel, block-randomized clinical trial, we administered commercially-available pomegranate polyphenol or placebo pills twice per day for one week to adult inpatients in a comprehensive rehabilitation setting starting approximately 2 weeks after stroke. Pills contained 1 g of polyphenols derived from whole pomegranate, equivalent to levels in approximately 8 oz of juice. Placebo pills were similar to the pomegranate pills except that they contained only lactose. Of the 163 patients that were screened, 22 were eligible and 16 were randomized (8 per group). We excluded one subject per group from the neuropsychological analyses since they were lost to follow-up, but we included all subjects in the analysis of functional data since outcome data were available. Clinicians and subjects were blinded to group assignment. Neuropsychological testing (primary outcome: Repeatable Battery for the Assessment of Neuropsychological Status) and functional independence scores were used to determine changes in cognitive and functional ability. Results: Pomegranate-treated subjects demonstrated more neuropsychological and functional improvement and spent less time in the hospital than placebo controls. Discussion: Pomegranate polyphenols enhanced cognitive and functional recovery after stroke, justifying pursuing larger clinical trials.

Low-dose proton radiation effects in a transgenic mouse model of Alzheimer's disease - Implications for space travel.

Space radiation represents a significant health risk for astronauts. Ground-based animal studies indicate that space radiation affects neuronal functions such as excitability, synaptic transmission, and plasticity, and it may accelerate the onset of Alzheimer's disease (AD). Although protons represent the main constituent in the space radiation spectrum, their effects on AD-related pathology have not been tested. We irradiated 3 month-old APP/PSEN1 transgenic (TG) and wild type (WT) mice with protons (150 MeV; 0.1-1.0 Gy; whole body) and evaluated functional and biochemical hallmarks of AD. We performed behavioral tests in the water maze (WM) before irradiation and in the WM and Barnes maze at 3 and 6 months post-irradiation to evaluate spatial learning and memory. We also performed electrophysiological recordings in vitro in hippocampal slices prepared 6 and 9 months post-irradiation to evaluate excitatory synaptic transmission and plasticity. Next, we evaluated amyloid ß (Aß) deposition in the contralateral hippocampus and adjacent cortex using immunohistochemistry. In cortical homogenates, we analyzed the levels of the presynaptic marker synaptophysin by Western blotting and measured pro-inflammatory cytokine levels (TNFα, IL-1ß, IL-6, CXCL10 and CCL2) by bead-based multiplex assay. TG mice performed significantly worse than WT mice in the WM. Irradiation of TG mice did not affect their behavioral performance, but reduced the amplitudes of population spikes and inhibited paired-pulse facilitation in CA1 neurons. These electrophysiological alterations in the TG mice were qualitatively different from those observed in WT mice, in which irradiation increased excitability and synaptic efficacy. Irradiation increased Aß deposition in the cortex of TG mice without affecting cytokine levels and increased synaptophysin expression in WT mice (but not in the TG mice). Although irradiation with protons increased Aß deposition, the complex functional and biochemical results indicate that irradiation effects are not synergistic to AD pathology.

Long-term effects of simulated microgravity and/or chronic exposure to low-dose gamma radiation on behavior and blood-brain barrier integrity.

Astronauts on lengthy voyages will be exposed to an environment of microgravity and ionizing radiation that may have adverse effects on physical abilities, mood, and cognitive functioning. However, little is known about the long-term effects of combined microgravity and low-dose radiation. We exposed mice to gamma radiation using a cobalt-57 plate (0.01 cGy/h for a total dose of 0.04 Gy), hindlimb unloading to simulate microgravity, or a combination of both for 3 weeks. Mice then underwent a behavioral test battery after 1 week, 1 month, 4 months, and 8 months to assess sensorimotor coordination/balance (rotarod), activity levels (open field), learned helplessness/depression-like behavior (tail suspension test), risk-taking (elevated zero maze), and spatial learning/memory (water maze). Aquaporin-4 (AQP4) expression was assessed in the brain after behavioral testing to determine blood-brain barrier (BBB) integrity. Mice that received unloading spent significantly more time in the exposed portions of the elevated zero maze, were hypoactive in the open field, and spent less time struggling on the tail suspension test than mice that did not receive unloading. Mice in the combination group expressed more AQP4 immunoactivity than controls. Elevated zero maze and AQP4 data were correlated. No differences were seen on the water maze or rotarod, and no radiation-only effects were observed. These results suggest that microgravity may lead to changes in exploratory/risk-taking behaviors in the absence of other sensorimotor or cognitive deficits and that combined microgravity and a chronic, low dose of gamma radiation may lead to BBB dysfunction.

A Single Low Dose of Proton Radiation Induces Long-Term Behavioral and Electrophysiological Changes in Mice.

Astronauts traveling outside Earth's magnetosphere risk exposure to charged particle radiation that may cause neurophysiological changes and behavioral deficits. Although proton particles comprise a large portion of the space radiation environment, little has been published on the effects of low-dose proton radiation on central nervous system function. In the current study, we irradiated young male mice with 0.5 Gy 150 MeV protons and assessed the effects on behavior and hippocampal neurophysiology. Spatial learning ability, a sensitive behavioral marker of hippocampal damage, was assessed using the water maze and Barnes maze before irradiation and repeatedly 3 and 6 months after irradiation. Evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes, long-term potentiation (LTP) and spontaneous oscillations (SOs) triggered by incubation with Mg(2+)-free media (reflecting interictal epileptiform activity) were assessed 9 months after irradiation in vitro in hippocampal slice preparations. Irradiated mice exhibited impaired reversal learning in the water maze compared to control mice 6 months after irradiation. Proton radiation did not affect LTP, but significantly increased fEPSP slopes and reduced the incidence of SOs 9 months after irradiation. These findings suggest that a single exposure to low-dose proton radiation can increase synaptic excitability and suppress the propensity for epileptiform activity. Such findings of functional alterations in the irradiated mouse hippocampus have implications for extended manned space missions planned in the near future.

Rat globus pallidus neurons: functional classification and effects of dopamine depletion.

The rat globus pallidus (GP) is homologous to the primate GP externus. Studies with injectable anesthetics suggest that GP neurons can be classified into Type-I and Type-II cells based on extracellularly recorded spike shape, or positively coupled (PC), negatively coupled (NC), and uncoupled (UC) cells based on functional connectivity with the cortex. In this study, we examined the electrophysiology of rat GP neurons using the inhalational anesthetic isoflurane which offers more constant and easily regulated levels of anesthesia than injectable anesthetics. In 130 GP neurons recorded using small-tip glass electrodes (<1 µm), all but one fired Type-II spikes (positive/negative waveform). Type-I cells were unlikely to be inhibited by isoflurane since all GP neurons also fired Type-II spikes under ketamine-induced anesthesia. When recorded with large-tip electrodes (∼2 µm), however, over 70% of GP neurons exhibited Type-I spikes (negative/positive waveform). These results suggest that the spike shape, recorded extracellularly, varies depending on the electrode used and is not reliable in distinguishing Type-I and Type-II neurons. Using dual-site recording, 40% of GP neurons were identified as PC cells, 17.5% NC cells, and 42.5% UC cells. The three subtypes also differed significantly in firing rate and pattern. Lesions of dopamine neurons increased the number of NC cells, decreased that of UC cells, and significantly shifted the phase relationship between PC cells and the cortex. These results support the presence of GP neuron subtypes and suggest that each subtype plays a different role in the pathophysiology of Parkinson's disease. Synapse 69:41-51, 2015. © 2014 Wiley Periodicals, Inc.

Posttraumatic reduction of edema with aquaporin-4 RNA interference improves acute and chronic functional recovery.

Traumatic brain injury (TBI) is common in young children and adolescents and is associated with long-term disability and mortality. The neuropathologic sequelae that result from juvenile TBI are a complex cascade of events that include edema formation and brain swelling. Brain aquaporin-4 (AQP4) has a key role in edema formation. Thus, development of novel treatments targeting AQP4 to reduce edema could lessen the neuropathologic sequelae. We hypothesized that inhibiting AQP4 expression by injection of small-interfering RNA (siRNA) targeting AQP4 (siAQP4) after juvenile TBI would decrease edema formation, neuroinflammation, neuronal cell death, and improve neurologic outcomes. The siAQP4 or a RNA-induced silencing complex (RISC)-free control siRNA (siGLO) was injected lateral to the trauma site after controlled cortical impact in postnatal day 17 rats. Magnetic resonance imaging, neurologic testing, and immunohistochemistry were performed to assess outcomes. Pups treated with siAQP4 showed acute (3 days after injury) improvements in motor function and in spatial memory at long term (60 days after injury) compared with siGLO-treated animals. These improvements were associated with decreased edema formation, increased microglial activation, decreased blood-brain barrier disruption, reduced astrogliosis and neuronal cell death. The effectiveness of our treatment paradigm was associated with a 30% decrease in AQP4 expression at the injection site.