A mitochondrial-targeted antioxidant (MitoQ) improves motor coordination and reduces Purkinje cell death in a mouse model of ARSACS.

Mitochondrial deficits have been observed in animal models of Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and in patient-derived fibroblasts. We investigated whether mitochondrial function could be restored in Sacs-/- mice, a mouse model of ARSACS, using the mitochondrial-targeted antioxidant ubiquinone MitoQ. After 10weeks of chronic MitoQ administration in drinking water, we partially reversed motor coordination deficits in Sacs-/- mice but did not affect litter-matched wild-type control mice. MitoQ administration led to a restoration of superoxide dismutase 2 (SOD2) in cerebellar Purkinje cell somata without altering Purkinje cell firing deficits. Purkinje cells in anterior vermis of Sacs-/- mice normally undergo cell death in ARSACS; however, Purkinje cells numbers were elevated after chronic MitoQ treatment. Furthermore, Purkinje cell innervation of target neurons in the cerebellar nuclei of Sacs-/- mice was also partially restored with MitoQ treatment. Our data suggest that MitoQ is a potential therapeutic treatment for ARSACS and that it improves motor coordination via increasing cerebellar Purkinje cell mitochondria function and reducing Purkinje cell death.

Pregnancy and childbirth during incarceration: A qualitative systematic review of lived experiences.

BACKGROUND: Incarcerated individuals who experience pregnancy or childbirth in correctional facilities face unique considerations for obstetric care and consequently are at greater risk of adverse maternal and fetal outcomes. OBJECTIVES: To characterise patient experiences regarding pregnancy and childbirth during incarceration via qualitative synthesis. SEARCH STRATEGY: Medline-OVID, EMBASE, CINAHL, Sociological Abstracts, Social Work Abstracts, Web of Science, Scopus and PsycInfo were systematically searched from inception to 24 December 2020. Supplementary searches were performed using the Scopus database. SELECTION CRITERIA: Only original, peer-reviewed literature was examined. Eligible studies were assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Qualitative Research. RESULTS: After screening 4173 original database citations, 24 studies that met inclusion criteria were included and analysed via thematic analysis. The 24 studies included perspectives from 645 female patients who had experienced incarceration, 69 healthcare providers and 70 prison staff. Key patient-reported concerns for the well-being of pregnant individuals during incarceration included mental health challenges, dehumanisation of prenatal care and delivery, lack of privacy, stigma, psychological trauma, lack of emotional support and shackle usage during pregnancy and/or labour. The studies reported a lack of support for patients to access female correctional officers or guards, privacy during intimate examinations, timely medical care and support for breastfeeding. Above all, the psychological trauma of separation from one's newborn after birth was of utmost devastation. CONCLUSIONS: Our systematic review highlights the dire need for accountability and interventions to improve pregnancy and childbirth care for incarcerated individuals. TWEETABLE ABSTRACT: This systematic review describes lived experiences of pregnancy & childbirth during incarceration, including dehumanisation, psychological trauma, and use of shackles.

The relation of childhood adversity and antisociality to suicide attempts in men admitted to forensic psychiatric hospital.

Suicide is a leading cause of death in custody. Although previous studies with prison inmates suggest a strong relation between childhood adversity and suicidal behavior, as well as between childhood adversity and antisociality, this has not been explored in the forensic psychiatric system. We compared 211 men admitted to a forensic hospital having a lifetime history of suicide attempts with 275 men with no suicide history in the same institution. Data were retrospectively coded from information gathered during their assessment and medical records. We examined associations of adverse childhood events and antisociality with suicide attempt history in a series of regression analyses. Childhood adversity was present in majority of individuals and significantly more common for individuals with a history of suicide attempts (76.8%) than those with no suicide attempts (63.3%). The suicide attempt group also experienced a greater number of adverse childhood events. Physical abuse, parental separation, and parental psychiatric history during childhood were associated with suicide attempts. Men with a suicide attempt history had higher antisociality scores than the comparison group and adult antisocial behavior partially mediated the relationship between adverse childhood experiences and suicide attempts. Men in forensic hospital who have suffered multiple experiences of childhood adversity are at increased risk for exhibiting antisocial behavior and engaging in suicidal attempts. Early interventions targeted toward antisociality and trauma-informed care in the forensic hospital are needed to support the mental health of the forensic population.

Repetitive transcranial magnetic stimulation (rTMS) in bipolar disorder: A systematic review.

OBJECTIVES: Repetitive transcranial magnetic stimulation (rTMS) is commonly used in unipolar depression; yet, its evidence in bipolar disorder (BD) is limited. We sought to review the evidence on the use of rTMS across the different stages of BD. METHODS: MEDLINE database was systematically searched using the PubMed interface following the PRISMA guidelines. Inclusion criteria were as follows: (i) randomized clinical trials (RCTs), open-label studies, and case series; (ii) specific evaluation of the treatment outcomes using psychometric scales; (iii) clinical studies in adults; and (iv) articles in the English language. The systematic review has been registered on PROSPERO (CRD42020192788). RESULTS: Thirty-one papers were included in the review. Most studies included participants diagnosed with a bipolar depressive episode (N = 24), have yielded mixed findings, and have yet to reach a consensus on the most effective rTMS protocol. Few studies examined the effect of rTMS during manic (N = 5) or mixed episode (N = 1), or as maintenance treatment (N = 1). The limited data thus far suggest rTMS to be relatively safe and well tolerated. Small sample sizes, heterogeneity among study designs, patients and control groups recruited, rTMS parameters, and outcome measures are among the most significant limitations to these studies. CONCLUSION: The current data regarding the application of rTMS in BD patients remain limited. More adequately powered sham-controlled studies are required to verify its efficacy. Large-scale clinical trials are needed to also determine whether its effects extend to manic and mixed episodes, as well as its role in mood stabilization and amelioration of suicidal behavior.

Tutors' Perceptions of the Transition to Video and Simulated Patients in Pre-clinical Psychiatry Training.

OBJECTIVE: The use of virtual learning in psychiatric education has been required to address COVID-19-related challenges. Research regarding the implementation of virtual teaching environments and standardized patients for simulation remains limited. Here, educators' outcomes were evaluated following a transition from in-person teaching with "real" patients, to a standardized patient-based simulation in pre-clerkship psychiatric clinical skills teaching for medical students. METHODS: The Integrated Clinical Experiences course at the University of Toronto is a pre-clerkship clinical skills curriculum for second-year medical students. Four psychiatric clinical skills sessions were transitioned from in-person teaching to virtual teaching environments with standardized patient-based simulation. Educators (tutors) were assigned to teach groups of four to seven medical students, with a total of 45 groups. Tutors were then asked to complete an online questionnaire, and data was analyzed by quantitative and qualitative means. RESULTS: Of 30 tutors, 21 (75.0%) had previously taught the course for an average of 6.52 ± 6.85 years. Twenty-four of 30 (80%) tutors described their ease of virtual teaching as "extremely easy" or "moderately easy". Twenty-three of 30 (76.6%) were "extremely satisfied" or "moderately satisfied" with standardized patient-based simulation. Various advantages and disadvantages of the virtual teaching environment with standardized patient-based simulation were identified. CONCLUSIONS: The transition to a virtual teaching environment utilizing standardized patients in a pre-clerkship simulation-based curriculum did not result in significant challenges that would limit educators' use of these teaching tools. Implementation of virtual teaching environments with standardized patients may thus serve to address challenges related to COVID-19 and resource limitations.

Altered interhemispheric signal propagation in schizophrenia and depression.

OBJECTIVE: Altered interhemispheric connectivity is implicated in the pathophysiology of schizophrenia (SCZ) and major depressive disorder (MDD) and may account for deficits in lateralized cognitive processes. We measured transcranial magnetic stimulation evoked interhemispheric signal propagation (ISP), a non-invasive measure of transcallosal connectivity, and hypothesized that the SCZ and MDD groups will have increased ISP compared to healthy controls. METHODS: We evaluated ISP over the dorsolateral prefrontal cortex in 34 patients with SCZ and 34 patients with MDD compared to 32 age and sex-matched healthy controls. RESULTS: ISP was significantly increased in patients with SCZ and patients with MDD compared to healthy controls but did not differ between patient groups. There were no effects of antidepressant, antipsychotic, and benzodiazepine medications on ISP and our results remained unchanged after re-analysis with a region of interest method. CONCLUSION: Altered ISP was found in both SCZ and MDD patient groups. This indicates that disruptions of interhemispheric signaling processes can be indexed with ISP across psychiatric populations. SIGNIFICANCE: These findings enhance our knowledge of the physiological mechanisms of interhemispheric imbalances in SCZ and MDD, which may serve as potential treatment targets in future patients.

Pharmacological mechanisms of interhemispheric signal propagation: a TMS-EEG study.

Interhemispheric connections across the corpus callosum have a predominantly inhibitory effect. Previous electrophysiology studies imply that local inhibitory circuits are responsible for inducing transcallosal inhibition, likely through inhibitory GABAB-mediated neurotransmission. We investigated the neurochemical mechanisms involved in interhemispheric connectivity by measuring transcranial magnetic stimulation (TMS)-induced interhemispheric signal propagation (ISP) in the motor cortex and dorsolateral prefrontal cortex (DLPFC) with electroencephalography (EEG) recordings under the pharmacological effects of baclofen, L-DOPA, dextromethorphan, and rivastigmine. We hypothesized that for both stimulated regions, GABAB receptor agonist baclofen would decrease ISP when compared against baseline while drugs that target other neurotransmitter systems (dopaminergic, acetylcholinergic, and glutamatergic systems) would have no effect on ISP. Twelve right-handed healthy volunteers completed this study and underwent TMS across five sessions in a randomized order. In the motor cortex, participants showed a significant decrease in ISP under baclofen, but not in the other drug conditions. There were no drug-induced changes in ISP in the DLPFC and baseline ISP did not differ across experimental sessions for both brain regions. Together, our results suggest that the inhibitory effects observed with interhemispheric signal transmission are mediated by a population of interneurons involving GABAB receptor neurotransmission. Inhibitory mechanisms of ISP may be more salient for motor-related functions in the motor cortex than for cognitive control in the DLPFC. These findings are a fundamental step in advancing our understanding of interhemispheric connectivity and may be used to identify treatments for disorders in which transcallosal transmission is dysfunctional.

The Current and Future Potential of Transcranial Magnetic Stimulation With Electroencephalography in Psychiatry.

The search for biological targets in psychiatric disorders is essential to better understand illness mechanisms and also to monitor and predict response to currently available therapeutic interventions. To this end, the combination of transcranial magnetic stimulation with electroencephalography (TMS-EEG) has emerged as a powerful clinical research tool. TMS-EEG allows cortical properties, such as excitability, inhibition, oscillatory activity, and connectivity, to be directly probed within a specific region of the cortex. This review will summarize the state of the current literature on TMS-EEG and its potential to uncover biological targets in psychiatric illnesses, with a focus on major depressive disorder, bipolar disorder, and schizophrenia. Collectively, the reviewed studies suggest that alterations in gamma-aminobutyric acid-mediated inhibition and gamma oscillations in the dorsolateral prefrontal cortex and neighboring frontal regions are potential shared biomarkers in psychiatry, highlighting the potential of TMS-EEG to help identify translational biomarkers.

Clinical utility and prospective of TMS-EEG.

Concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) has emerged as a powerful tool to non-invasively probe brain circuits in humans, allowing for the assessment of several cortical properties such as excitability and connectivity. Over the past decade, this technique has been applied to various clinical populations, enabling the characterization and development of potential TMS-EEG predictors and markers of treatments and of the pathophysiology of brain disorders. The objective of this article is to present a comprehensive review of studies that have used TMS-EEG in clinical populations and to discuss potential clinical applications. To provide a technical and theoretical framework, we first give an overview of TMS-EEG methodology and discuss the current state of knowledge regarding the use of TMS-EEG to assess excitability, inhibition, plasticity and connectivity following neuromodulatory techniques in the healthy brain. We then review the insights afforded by TMS-EEG into the pathophysiology and predictors of treatment response in psychiatric and neurological conditions, before presenting recommendations for how to address some of the salient challenges faced in clinical TMS-EEG research. Finally, we conclude by presenting future directions in line with the tremendous potential of TMS-EEG as a clinical tool.

Altered synaptic and firing properties of cerebellar Purkinje cells in a mouse model of ARSACS.

KEY POINTS: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative human disease characterized in part by ataxia and Purkinje cell loss in anterior cerebellar lobules. A knock-out mouse model has been developed that recapitulates several features of ARSACS. Using this ARSACS mouse model, we report changes in synaptic input and intrinsic firing in cerebellar Purkinje cells, as well as in their synaptic output in the deep cerebellar nuclei. Changes in firing are observed in anterior lobules that later exhibit Purkinje cell death, but not in posterior lobules that do not. Our results show that both synaptic and intrinsic alterations in Purkinje cell properties likely contribute to disease manifestation in ARSACS; these findings resemble pathophysiological changes reported in several other ataxias. ABSTRACT: Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes a pronounced and progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the Sacs gene that encodes the protein sacsin. To better understand the cerebellar pathophysiology in ARSACS, we studied synaptic and firing properties of Purkinje cells from a mouse model of ARSACS, Sacs-/- mice. We found that excitatory synaptic drive was reduced onto Sacs-/- Purkinje cells, and that Purkinje cell firing rate, but not regularity, was reduced at postnatal day (P)40, an age when ataxia symptoms were first reported. Firing rate deficits were limited to anterior lobules that later display Purkinje cell death, and were not observed in posterior lobules where Purkinje cells are not lost. Mild firing deficits were observed as early as P20, prior to the manifestation of motor deficits, suggesting that a critical level of cerebellar dysfunction is required for motor coordination to emerge. Finally, we observed a reduction in Purkinje cell innervation onto target neurons in the deep cerebellar nuclei (DCN) in Sacs-/- mice. Together, these findings suggest that multiple alterations in the cerebellar circuit including Purkinje cell input and output contribute to cerebellar-related disease onset in ARSACS.

Influence of inter-train interval on the plastic effects of rTMS.

BACKGROUND: High frequency repetitive transcranial magnetic stimulation (rTMS) elicits plastic effects in excitatory and inhibitory circuits. Inter-train intervals (ITI) were initially incorporated into rTMS paradigms to avoid overheating and for safety considerations. Recent studies have shown that inclusion of ITI, as opposed to continuous stimulation, is essential for eliciting excitatory effects, but the optimal ITI remains unknown. Moreover, if ITI duration has no effect, it may be possible to substantially reduce treatment time for rTMS. HYPOTHESIS: ITI duration modulates the excitatory and disinhibitory effects of rTMS. METHODS: rTMS (20 Hz, 2 s trains, 1200 pulses, 100% RMT) was applied in 14 healthy individuals with ITI of 4s (duration: ∼3 min), 8s (∼5 min), 16s (∼9 min) or 32s (16.5 min) in sessions separated by ≥5 days. Effects on cortical excitability and GABAA receptor mediated short interval intracortical inhibition (SICI) were measured for 75 min following rTMS. RESULTS: The time-course of increased cortical excitability following rTMS was independent of ITI duration. There was a striking influence of ITI on SICI, whereby disinhibition increased with shorter ITI duration. Changes in cortical excitability and SICI were independent of each other. CONCLUSION: These findings provide the first evidence to suggest that ITI may be substantially shortened without loss of rTMS effects, and warrant further investigation where rTMS is applied therapeutically. Furthermore, shorter ITIs result in greater disinhibitory effects which may be desirable in some clinical disorders and accelerated treatment paradigms. The tuning of the plasticity of cortical excitatory and inhibitory circuits to rTMS parameters in human cortex are independent.