Breathing control training for functional seizures: A multi-site, open-label pilot study.

There are no well-validated treatments for functional seizures. While specialist psychotherapy is usually recommended, the evidence for its benefit is qualified, and it can be difficult to obtain. Given the association between hyperventilation and functional seizures we explored an alternative modality, breathing control training, in a multi-site open label pilot trial. Participants with functional seizures over the age of 16 received an hour of breathing training from a respiratory physiotherapist, with a half-hour booster session a month later. Seizure frequency and Nijmegen scores (a measure of hyperventilation) were reported at baseline and follow-up, 3-4 months later. Eighteen subjects were recruited, and 10 completed follow-up. Seven of these 10 had improved seizure frequency, and 3 did not (Wilcoxon signed rank test, p = 0.09), with seizure frequency correlating with Nijmegen score (Spearman's rank correlation = 0.75, p = 0.034). The intervention was well tolerated, with no adverse events reported. These preliminary results support a potentially new approach to treating functional seizures that should prove cost-effective and acceptable, though require confirmation by a randomised controlled trial.

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.

Hypnosis and suggestion as interventions for functional neurological disorder: A systematic review.

OBJECTIVE: Functional neurological disorder (FND) involves the presence of neurological symptoms that cannot be explained by neurological disease. FND has long been linked to hypnosis and suggestion, both of which have been used as treatments. Given ongoing interest, this review examined evidence for the efficacy of hypnosis and suggestion as treatment interventions for FND. METHOD: A systematic search of bibliographic databases was conducted to identify group studies published over the last hundred years. No restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, extracted data, and rated study quality. RESULTS: The search identified 35 studies, including 5 randomised controlled trials, 2 non-randomised trials, and 28 pre-post studies. Of 1584 patients receiving either intervention, 1379 (87%) showed significant improvements, including many who demonstrated resolution of their symptoms in the short-term. Given the heterogeneity of interventions and limitations in study quality overall, more formal quantitative synthesis was not possible. CONCLUSIONS: The findings highlight longstanding and ongoing interest in using hypnosis and suggestion as interventions for FND. While the findings appear promising, limitations in the evidence base, reflecting limitations in FND research more broadly, prevent definitive recommendations. Further research seems warranted given these supportive findings.

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.

A multi-centre, double-blind, 12-week, randomized, placebo-controlled trial of adjunctive N-Acetylcysteine for treatment-resistant PTSD.

BACKGROUND: PTSD may involve oxidative stress, and N-acetylcysteine (NAC) may reduce the impact of oxidative stress in the brain. This study aims to investigate the efficacy of adjuvant NAC in people with treatment-resistant PTSD. METHODS: A multicentre, randomised, double-blind, placebo-controlled trial for adults with PTSD unresponsive to first-line treatment. The intervention was either oral NAC 2.7 g/day or placebo for 12 weeks. The primary outcome was change in Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) at 12 weeks compared with baseline. Secondary outcomes included depression and substance craving. Follow-up measures were obtained at 16 and 64-weeks. RESULTS: 133 patients were assessed, with 105 randomised; 81 participants completed the 12-week trial, 79 completed week-16 follow-up, and 21 completed week-64 follow-up. There were no significant differences between those taking NAC and those taking placebo in CAPS-5 scores at week 12, nor in secondary outcomes. Significant between-group differences were observed at week 64 in craving duration (Cohen's d = 1.61) and craving resistance (Cohen's d = 1.03), both in favour of NAC. CONCLUSION: This was the first multicentre, double-blind, randomised, placebo-controlled trial of adjunctive NAC for treatment-resistant PTSD. No benefit of NAC was observed in this group beyond that provided by placebo at end of the trial. TRIAL REGISTRATION: ACTRN12618001784202, retrospectively registered 31/10/2018, URL: http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376004.

Principles for delivering improved care of people with functional seizures: Closing the treatment gap.

Patients diagnosed with functional (psychogenic nonepileptic) seizures have similar or greater levels of disability, morbidity and mortality than people with epilepsy, but there are far fewer treatment services. In contrast to epilepsy, the current understanding of pathophysiological mechanisms and the development of evidence-based treatments for functional seizures is rudimentary. This leads to high direct healthcare costs and high indirect costs to the patient, family and wider society. There are many patient, clinician and system-level barriers to improving outcomes for functional seizures. At a patient level, these include the heterogeneity of symptoms, diagnostic uncertainty, family factors and difficulty in perceiving psychological aspects of illness and potential benefits of treatment. Clinician-level barriers include sub-specialism, poor knowledge, skills and attitudes and stigma. System-level barriers include the siloed nature of healthcare, the high prevalence of functional seizures and funding models relying on individual medical practitioners. Through the examination of international examples and expert recommendations, several themes emerge that may address some of these barriers. These include (1) stepped care with low-level, brief generalised interventions, proceeding to higher level, extended and individualised treatments; (2) active triage of complexity, acuity and treatment readiness; (3) integrated interdisciplinary teams that individualise formulation, triage, and treatment planning and (4) shared care with primary, emergency and community providers and secondary consultation. Consideration of the application of these principles to the Australian and New Zealand context is proposed as a significant opportunity to meet an urgent need.

Improving the treatment of functional seizures through a public specialist outpatient clinic.

OBJECTIVES: We performed an audit of the first 12 months of clinical operations to assess the feasibility of a newly established public outpatient clinic for the assessment and treatment of functional (psychogenic nonepileptic) seizures (FS). METHOD: Clinical notes for the first 12 months of the FSclinic weresystematicallyreviewed with data compiled onreferral pathways, clinic attendance, clinical features, treatments, and outcomes. RESULTS: Of eighty-two new FS patients referred to the clinic, over 90% attended. Patients were diagnosed with FS after comprehensive epileptological and neuropsychiatric review, mostly with typical seizure-like episodes captured during video-EEG monitoring, and most accepted the diagnosis. Most had FS at least weekly, with little sense of control and significant impairment. The majority of individuals had significant psychiatric and medical comorbidity. Predisposing, precipitating, and perpetuating factors were readily identified in >90% of cases. Of 52 patients with follow-up data within12 months, 88% were either stable or improved in terms of the control of their FS. CONCLUSION: The Alfred functional seizure clinic model, the first dedicated public outpatient clinic for FS in Australia, provides a feasible and potentially effective treatment pathway for this underserved and disabled patient group.

Efficacy of Cognitive-Behavioral Therapy Targeting Severe Fatigue Following Coronavirus Disease 2019: Results of a Randomized Controlled Trial.

BACKGROUND: Severe fatigue following coronavirus disease 2019 (COVID-19) is prevalent and debilitating. This study investigated the efficacy of cognitive-behavioral therapy (CBT) for severe fatigue following COVID-19. METHODS: A multicenter, 2-arm randomized controlled trial was conducted in the Netherlands with patients being severely fatigued 3-12 months following COVID-19. Patients (N = 114) were randomly assigned (1:1) to CBT or care as usual (CAU). CBT, targeting perpetuating factors of fatigue, was provided for 17 weeks. The primary outcome was the overall mean difference between CBT and CAU on the fatigue severity subscale of the Checklist Individual Strength, directly post-CBT or CAU (T1), and after 6 months (T2). Secondary outcomes were differences in proportions of patients meeting criteria for severe and/or chronic fatigue, differences in physical and social functioning, somatic symptoms, and problems concentrating between CBT and CAU. RESULTS: Patients were mainly nonhospitalized and self-referred. Patients who received CBT were significantly less severely fatigued across follow-up assessments than patients receiving CAU (-8.8 [95% confidence interval {CI}, -11.9 to -5.8]); P < .001), representing a medium Cohen's d effect size (0.69). The between-group difference in fatigue severity was present at T1 (-9.3 [95% CI, -13.3 to -5.3]) and T2 (-8.4 [95% CI, -13.1 to -3.7]). All secondary outcomes favored CBT. Eight adverse events were recorded during CBT, and 20 during CAU. No serious adverse events were recorded. CONCLUSIONS: Among patients, who were mainly nonhospitalized and self-referred, CBT was effective in reducing fatigue. The positive effect was sustained at 6-month follow-up. CLINICAL TRIALS REGISTRATION: Netherlands Trial Register NL8947.

Feedback-loop between psychotic symptoms and brain volume: A cross-lagged panel model study.

Brain structural changes are known to be associated with psychotic symptoms, with worse symptoms consistently associated with brain volume loss in some areas. It is not clear whether volume and symptoms interfere with each other over the course of psychosis. In this paper, we analyse the temporal relationships between psychosis symptom severity and total gray matter volume. We applied a cross-lagged panel model to a public dataset from the NUSDAST cohorts. The subjects were assessed at three-time points: baseline, 24 months, and 48 months. Psychosis symptoms were measured by SANS and SAPS scores. The cohort contained 673 subjects with schizophrenia, healthy subjects and their siblings. There were significant effects of symptom severity on total gray matter volume and vice-versa. The worse the psychotic symptoms, the smaller the total gray volume, and the smaller the volume, the worse the symptomatology. There is a bidirectional temporal relationship between symptoms of psychosis and brain volume.

A growing understanding of the role of muscarinic receptors in the molecular pathology and treatment of schizophrenia.

Pre-clinical models, postmortem and neuroimaging studies all support a role for muscarinic receptors in the molecular pathology of schizophrenia. From these data it was proposed that activation of the muscarinic M1 and/or M4 receptor would reduce the severity of the symptoms of schizophrenia. This hypothesis is now supported by results from two clinical trials which indicate that activating central muscarinic M1 and M4 receptors can reduce the severity of positive, negative and cognitive symptoms of the disorder. This review will provide an update on a growing body of evidence that argues the muscarinic M1 and M4 receptors have critical roles in CNS functions that are dysregulated by the pathophysiology of schizophrenia. This realization has been made possible, in part, by the growing ability to visualize and quantify muscarinic M1 and M4 receptors in the human CNS using molecular neuroimaging. We will discuss how these advances have provided evidence to support the notion that there is a sub-group of patients within the syndrome of schizophrenia that have a unique molecular pathology driven by a marked loss of muscarinic M1 receptors. This review is timely, as drugs targeting muscarinic receptors approach clinical use for the treatment of schizophrenia and here we outline the background biology that supported development of such drugs to treat the disorder.

Functional Gait Disorders: Clinical presentations, Phenotypes and Implications for treatment.

BACKGROUND: Functional Gait Disorders (FGD) are a common presentation of motor-Functional Neurological Disorders (motor-FND) that affect walking ability. AIM: To provide a narrative review of the current literature on FGD. METHODS: A narrative overview of published literature was undertaken, based on a systematic search of relevant databases, authoritative texts and citation tracking. RESULTS: FGD is multidimensional and disabling, with numerous phenotypes described in the literature, including 'knee buckling,' 'astasia-abasia' and 'excessive slowness.' Motor symptoms such as weakness or tremor, and non-motor symptoms, such as pain and fatigue may contribute to the disability and distress in FGD. Phenotypic features and clinical signs are seen in FGD that demonstrate inconsistency and incongruity with structural disease. A limited number of treatment studies have specifically focussed on FGD, however, reporting of outcomes from motor-FND cohorts has demonstrated short and long-term improvements in walking ability through multidisciplinary rehabilitation. CONCLUSIONS: The relative contribution of motor and non-motor symptoms in FGD remains unknown, but it is likely that non-motor symptoms increase the illness burden and should be considered during assessment and treatment. Recommended treatment for FGD involves multidisciplinary rehabilitation, but optimum treatment elements are yet to be determined.

Main and moderated effects of multimorbidity and depressive symptoms on cognition

Objective: Multimorbidity, or the occurrence of two or more chronic conditions, is a global challenge, with implications for mortality, morbidity, disability, and life quality. Psychiatric disorders are common among the chronic diseases that affect patients with multimorbidity. It is still not well understood whether psychiatric symptoms, especially depressive symptoms, moderate the effect of multimorbidity on cognition. Methods: We used a large (n=2,681) dataset to assess whether depressive symptomatology moderates the effect of multimorbidity on cognition using structural equation modelling. Results: It was found that the more depressive symptoms and chronic conditions, the worse the cognitive performance, and the higher the educational level, the better the cognitive performance. We found a significant but weak (0.009; p = 0.04) moderating effect. Conclusion: We have provided the first estimate of the moderating effect of depression on the relation between multimorbidity and cognition, which was small. Although this moderation has been implied by many previous studies, it was never previously estimated.

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.

Anaesthesia and the development of functional neurological disorder: A systematic review and case series.

OBJECTIVE: There are reports of functional neurological disorder (FND) developing after anaesthesia, though separating any aetiological role from other possible factors is challenging. We aimed to systematically review all published cases of post-anaesthetic FND to see if any common factors supported an anaesthetic role. We also aimed to identify all cases of post-anaesthetic FND arising in our FND clinic, to obtain an estimate of its frequency. METHODS: For the review, a systematic search for published cases of FND developing within 48 h of anaesthesia was conducted in June 2022. For the case series, the medical records of all patients attending an FND clinic in Melbourne between 2017 and 2019 were examined, and all cases with FND within 48 h of anaesthesia extracted. RESULTS: 36 published cases were identified for the review. Sixteen described preceding stressors and 16 psychiatric diagnoses, including 8 with previous FND. Thirty-two (92%) had undergone general anaesthesia, most commonly for obstetric procedures. Motor/sensory loss was the most common presentation, followed by seizures and coma. Most (80.5%) developed symptoms immediately on induction or cessation of anaesthesia. For the case series, 8 of 107 clinic patients (7.5%), developed FND within 48 h of anaesthesia. All had previous psychiatric diagnoses, including 3 with previous FND. Three underwent general anaesthesia and 3 procedural sedation, with seizures the most common presentation. All developed symptoms immediately on induction or cessation of anaesthesia. CONCLUSION: These cases provide some support for an aetiological role for anaesthesia: there is evidence for an anaesthetic 'model' for the symptoms of FND that arise, they largely arise with the onset or termination of anaesthesia, and they arise most frequently during general anaesthesia or sedation.

Multimorbidity worsened anxiety and depression symptoms during the COVID-19 pandemic in Brazil.

Multimorbidity is a global health issue impacting the quality of life of all ages. Multimorbidity with a mental disorder is little studied and is likely to have been affected by the COVID-19 pandemic. We used a survey of 14,007 respondents living in Brazil to investigate whether people who already had at least one chronic medical condition had more depression and anxiety symptoms during social distancing in 2020. Generalized linear models and structural equation modelling were used to estimate the effects. A 19 % and 15 % increase in depressive symptoms were found in females and males, respectively, for each unit of increase in the observed value of reported chronic disease. Older subjects presented fewer symptoms of depression and anxiety. There was a 16 % increase in anxiety symptoms in females for each unit increase in the reported chronic disease variable and a 14 % increase in males. Younger subjects were more affected by anxiety symptoms in a dose-response fashion. High income was significantly related to fewer depressive and anxiety symptoms in both males and females. Physical activity was significantly associated with fewer anxiety and depression symptoms. Structural equation modelling confirmed these results and provided further insight into the hypothesised paths.

Hyperventilation in functional seizures: Evidence for subtypes.

PURPOSE: Functional seizures (FS) are heterogenous, with no agreed way to subdivide them. One FS subtype frequently observed during EEG is those whose seizures are provoked by hyperventilation. We wished to see whether this subtype might reflect a different seizure mechanism. METHODS: We analysed the video-EEG/ECGs of all patients with FS from two hospitals in Melbourne from 2010-6. RESULTS: We identified 120 patients during the study period, 107 of whom had usable recordings. Examining those 11 (10%) whose seizures had been induced by hyperventilation, we compared the heart rates of those where the seizure occurred during the hyperventilation, and those where they occurred afterwards. The during-hyperventilation group had a higher baseline heart rate which increased prior to their seizure; the after-hyperventilation group had a lower baseline heart rate and no pre-ictal increase. In those patients whose seizures were not hyperventilation-induced, the same two heart rate patterns could be found: those with a higher baseline heart rate showed increasing heart rate prior to seizure onset, while those with a lower baseline heart rate did not. Cluster analysis showed the sample was optimally divided into these two groups based on their pre-onset heart rate alone. CONCLUSION: Patients with FS show two distinct patterns of pre-ictal heart rate, which may reflect two distinct seizure mechanisms.