Detection of capillary abnormalities in early diabetic retinopathy using scanning laser ophthalmoscopy and optical coherence tomography combined with adaptive optics.

This study tested if a high-resolution, multi-modal, multi-scale retinal imaging instrument can provide novel information about structural abnormalities in vivo. The study examined 11 patients with very mild to moderate non-proliferative diabetic retinopathy (NPDR) and 10 healthy subjects using fundus photography, optical coherence tomography (OCT), OCT angiography (OCTA), adaptive optics scanning laser ophthalmoscopy (AO-SLO), adaptive optics OCT and OCTA (AO-OCT(A)). Of 21 eyes of 11 patients, 11 had very mild NPDR, 8 had mild NPDR, 2 had moderate NPDR, and 1 had no retinopathy. Using AO-SLO, capillary looping, inflections and dilations were detected in 8 patients with very mild or mild NPDR, and microaneurysms containing hyperreflective granular elements were visible in 9 patients with mild or moderate NPDR. Most of the abnormalities were seen to be perfused in the corresponding OCTA scans while a few capillary loops appeared to be occluded or perfused at a non-detectable flow rate, possibly because of hypoperfusion. In one patient with moderate NPDR, non-perfused capillaries, also called ghost vessels, were identified by alignment of corresponding en face AO-OCT and AO-OCTA images. The combination of multiple non-invasive imaging methods could identify prominent microscopic abnormalities in diabetic retinopathy earlier and more detailed than conventional fundus imaging devices.

Retinal OCT speckle as a biomarker for glaucoma diagnosis and staging.

This paper presents a novel image analysis strategy that increases the potential of macular Optical Coherence Tomography (OCT) by using speckle features as biomarkers in different stages of glaucoma. A large pool of features (480) were computed for a subset of macular OCT volumes of the Leuven eye study cohort. The dataset contained 258 subjects that were divided into four groups based on their glaucoma severity: Healthy (56), Mild (94), Moderate (48), and Severe (60). The OCT speckle features were categorized as statistical properties, statistical distributions, contrast, spatial gray-level dependence matrices, and frequency domain features. The averaged thicknesses of ten retinal layers were also collected. Kruskal-Wallis H test and multivariable regression models were used to infer the most significant features related to glaucoma severity classification and to the correlation with visual field mean deviation. Four features were selected as being the most relevant: the ganglion cell layer (GCL) and the inner plexiform layer (IPL) thicknesses, and two OCT speckle features, the data skewness computed on the retinal nerve fiber layer (RNFL) and the scale parameter (a) of the generalized gamma distribution fitted to the GCL data. Based on a significance level of 0.05, the regression models revealed that RNFL skewness exhibited the highest significance among the features considered for glaucoma severity staging (p-values of 8.6×10-6 for the logistic model and 2.8×10-7 for the linear model). Furthermore, it demonstrated a strong negative correlation with the visual field mean deviation (ρ=-0.64). The post hoc analysis revealed that, when distinguishing healthy controls from glaucoma subjects, GCL thickness is the most relevant feature (p-value of 8.7×10-5). Conversely, when comparing the Mild versus Moderate stages of glaucoma, RNFL skewness emerged as the only feature exhibiting statistical significance (p-value = 0.001). This work shows that macular OCT speckle contains information that is currently not used in clinical practice, and not only complements structural measurements (thickness) but also has a potential for glaucoma staging.

Multi-modal and multi-scale clinical retinal imaging system with pupil and retinal tracking.

We present a compact multi-modal and multi-scale retinal imaging instrument with an angiographic functional extension for clinical use. The system integrates scanning laser ophthalmoscopy (SLO), optical coherence tomography (OCT) and OCT angiography (OCTA) imaging modalities and provides multi-scale fields of view. For high resolution, and high lateral resolution in particular, cellular imaging correction of aberrations by adaptive optics (AO) is employed. The entire instrument has a compact design and the scanning head is mounted on motorized translation stages that enable 3D self-alignment with respect to the subject's eye by tracking the pupil position. Retinal tracking, based on the information provided by SLO, is incorporated in the instrument to compensate for retinal motion during OCT imaging. The imaging capabilities of the multi-modal and multi-scale instrument were tested by imaging healthy volunteers and patients.

Automatic Segmentation of the Optic Nerve Head Region in Optical Coherence Tomography: A Methodological Review.

The optic nerve head (ONH) represents the intraocular section of the optic nerve, which is prone to damage by intraocular pressure (IOP). The advent of optical coherence tomography (OCT) has enabled the evaluation of novel ONH parameters, namely the depth and curvature of the lamina cribrosa (LC). Together with the Bruch's membrane minimum-rim-width (BMO-MRW), these seem to be promising ONH parameters for diagnosis and monitoring of retinal diseases such as glaucoma. Nonetheless, these OCT derived biomarkers are mostly extracted through manual segmentation, which is time-consuming and prone to bias, thus limiting their usability in clinical practice. The automatic segmentation of ONH in OCT scans could further improve the current clinical management of glaucoma and other diseases. This review summarizes the current state-of-the-art in automatic segmentation of the ONH in OCT. PubMed and Scopus were used to perform a systematic review. Additional works from other databases (IEEE, Google Scholar and ARVO IOVS) were also included, resulting in a total of 29 reviewed studies. For each algorithm, the methods, the size and type of dataset used for validation, and the respective results were carefully analysed. The results show a lack of consensus regarding the definition of segmented regions, extracted parameters and validation approaches, highlighting the importance and need of standardized methodologies for ONH segmentation. Only with a concrete set of guidelines, these automatic segmentation algorithms will build trust in data-driven segmentation models and be able to enter clinical practice.

Signal-carrying speckle in optical coherence tomography: a methodological review on biomedical applications.

SIGNIFICANCE: Speckle has historically been considered a source of noise in coherent light imaging. However, a number of works in optical coherence tomography (OCT) imaging have shown that speckle patterns may contain relevant information regarding subresolution and structural properties of the tissues from which it is originated. AIM: The objective of this work is to provide a comprehensive overview of the methods developed for retrieving speckle information in biomedical OCT applications. APPROACH: PubMed and Scopus databases were used to perform a systematic review on studies published until December 9, 2021. From 146 screened studies, 40 were eligible for this review. RESULTS: The studies were clustered according to the nature of their analysis, namely static or dynamic, and all features were described and analyzed. The results show that features retrieved from speckle can be used successfully in different applications, such as classification and segmentation. However, the results also show that speckle analysis is highly application-dependant, and the best approach varies between applications. CONCLUSIONS: Several of the reviewed analyses were only performed in a theoretical context or using phantoms, showing that signal-carrying speckle analysis in OCT imaging is still in its early stage, and further work is needed to validate its applicability and reproducibility in a clinical context.

Adaptive optics ophthalmoscopy: a systematic review of vascular biomarkers.

Retinal vascular diseases are a leading cause for blindness and partial sight certifications. By applying adaptive optics (AO) to conventional imaging modalities, the microstructures of the retinal vasculature can be observed with high spatial resolution, hence offering a unique opportunity for the exploration of the human microcirculation. The objective of this systematic review is to describe the current state of retinal vascular biomarkers imaged by AO flood illumination ophthalmoscopy (FIO) and AO scanning laser ophthalmoscopy (SLO). A literature research was conducted in the PubMed and Scopus databases on July 9, 2020. From 217 screened studies, 42 were eligible for this review. All studies underwent a quality check regarding their content. A meta-analysis was performed for the biomarkers reported for the same pathology in at least three studies using the same modality. The most frequently studied vascular biomarkers were the inner diameter (ID), outer diameter (OD), parietal thickness (PT), wall cross-sectional area (WCSA), and wall-to-lumen ratio (WLR). The applicability of AO vascular biomarkers has been mostly explored in systemic hypertension using AO FIO and in diabetes using AO SLO. The result of the meta-analysis for hypertensive patients showed that WLR, PT, and ID were significantly different when compared to healthy controls, while WCSA was not (P < 0.001, P = 0.002, P < 0.001, and P = 0.070, respectively). The presented review shows that, although a substantial number of retinal vascular biomarkers have been explored in AO en face imaging, further clinical research and standardization of procedures is needed to validate such biomarkers for the longitudinal monitoring of arterial hypertension and other diseases.

Tear Film Surface Quality in Modern Daily Disposable Contact Lens Wear.

OBJECTIVES: As reported previously, tear film surface quality (TFSQ) should be considered in contact lens (CL) fitting. This study followed noninvasive keratograph tear film break-up time (NIKBUT) in CL wearers for 12 months to validate its clinical utility in predicting CL performance. METHODS: Fifty-five subjects (M/F=17/38) aged 26±4 years were prescribed silicone hydrogel or hydrogel CLs. The study included baseline measurements without CLs; 2 visits for CL fitting and control; follow-up after 3, 6, and 12 months of CL wear; and postwear visit without CLs. Ocular Surface Disease Index (OSDI), 8-Item Contact Lens Dry Eye Questionnaire (CLDEQ-8), first and mean NIKBUT (F/M-NIKBUT), fluorescein tear film break-up time (FBUT), and ocular surface staining were evaluated. RESULTS: Post hoc analysis of each pair of visits showed differences between baseline and all CL visits for F-NIKBUT, M-NIKBUT, FBUT, and corneal staining. No difference was reported in symptoms. In addition, differences between baseline and postwear visits were noted in OSDI, M-NIKBUT, FBUT, and corneal staining, with three of the latter parameters showing a downward trend. CONCLUSIONS: No changes in TFSQ and symptoms were reported over 12 months. Introducing NIKBUT as part of routine CL fitting is advised to improve CL fit and predict success.

Corneal Optical Coherence Tomography Speckle in Crosslinked and Untreated Rabbit Eyes in Response to Elevated Intraocular Pressure.

Purpose: To ascertain the influence of intraocular pressure (IOP) on corneal optical coherence tomography (OCT) speckle in untreated and ultraviolet A-riboflavin induced corneal collagen crosslinked rabbit eyes. Methods: Left corneas of eight rabbits were de-epithelialized and crosslinked by applying riboflavin and 30-minute ultraviolet A light exposure. After enucleation (6 months after treatment), each eyeball (treated and untreated) was mounted in a measurement setup, in which IOP was increased from 15 to 45 mm Hg in steps of 5 mm Hg. At each IOP value, single B-scans of the central cornea were acquired three times with the spectral-domain OCT Copernicus-HR. Then, three regions of interest, including the anterior, posterior, and entire corneal stroma, were automatically extracted. Five different probability distributions were used as a model for the corneal speckle and the one with the best goodness of fit was chosen for further analysis. Results: The generalized gamma distribution achieved the best goodness of fit and its scale (a) and shape (v) parameters statistically significantly changed with increasing IOP in the three regions of analysis (two-way repeated measures analysis of variance, all P < 0.05). The statistically significant difference between untreated and crosslinked eyes was observed for the shape parameters of the posterior and entire corneal stroma. Conclusions: Corneal OCT speckle is influenced by IOP and shows to be significantly different in untreated and crosslinked eyes. Corneal OCT speckle analysis has the potential to be indirectly used for assessing changes in corneal stroma in ex vivo and in vivo studies. Translational Relevance: Investigation of corneal OCT speckle statistics can offer additional diagnostic biomarkers related to changes in the corneal stroma after ocular surgeries.

Optical Coherence Tomography Imaging of the Lamina Cribrosa: Structural Biomarkers in Nonglaucomatous Diseases.

The lamina cribrosa (LC) is an active structure that responds to the strain by changing its morphology. Abnormal changes in LC morphology are usually associated with, and indicative of, certain pathologies such as glaucoma, intraocular hypertension, and myopia. Recent developments in optical coherence tomography (OCT) have enabled detailed in vivo studies about the architectural characteristics of the LC. Structural characteristics of the LC have been widely explored in glaucoma management. However, information about which LC biomarkers could be useful for the diagnosis, and follow-up, of other diseases besides glaucoma is scarce. Hence, this literature review aims to summarize the role of the LC in nonophthalmic and ophthalmic diseases other than glaucoma. PubMed was used to perform a systematic review on the LC features that can be extracted from OCT images. All imaging features are presented and discussed in terms of their importance and applicability in clinical practice. A total of 56 studies were included in this review. Overall, LC depth (LCD) and thickness (LCT) have been the most studied features, appearing in 75% and 45% of the included studies, respectively. These biomarkers were followed by the prelaminar tissue thickness (21%), LC curvature index (5.4%), LC global shape index (3.6%), LC defects (3.6%), and LC strains/deformations (1.8%). Overall, the disease groups showed a thinner LC (smaller LCT) and a deeper ONH cup (larger LCD), with some exceptions. A large variability between approaches used to compute LC biomarkers has been observed, highlighting the importance of having automated and standardized methodologies in LC analysis. Moreover, further studies are needed to identify the pathologies where LC features have a diagnostic and/or prognostic value.

OCTA Multilayer and Multisector Peripapillary Microvascular Modeling for Diagnosing and Staging of Glaucoma.

Purpose: To develop and assess an automatic procedure for classifying and staging glaucomatous vascular damage based on optical coherence tomography angiography (OCTA) imaging. Methods: OCTA scans (Zeiss Cirrus 5000 HD-OCT) from a random eye of 39 healthy subjects and 82 glaucoma patients were used to develop a new classification algorithm based on multilayer and multisector information. The averaged circumpapillary retinal nerve fiber layer (RNFL) thickness was also collected. Three models, support vector machine (SVM), random forest (RF), and gradient boosting (xGB), were developed and optimized for classifying between healthy and glaucoma patients, primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG), and glaucoma severity groups. Results: All the models, the SVM (area under the receiver operating characteristic [AUROC] 0.89 ± 0.06), the RF (AUROC 0.86 ± 0.06), and the xGB (AUROC 0.85 ± 0.07), with 26, 22, and 29 vascular features obtained after feature selection, respectively, presented a similar performance to the RNFL thickness (AUROC 0.85 ± 0.06) in classifying healthy and glaucoma patients. The superficial vascular plexus was the most informative layer with the infero temporal sector as the most discriminative region of interest. No significant differentiation was obtained in discriminating the POAG from the NTG group. The xGB model, after feature selection, presented the best performance in classifying the severity groups (AUROC 0.76 ± 0.06), outperforming the RNFL (AUROC 0.67 ± 0.06). Conclusions: OCTA multilayer and multisector information has similar performance to RNFL for glaucoma diagnosis, but it has an added value for glaucoma severity classification, showing promising results for staging glaucoma progression. Translational Relevance: OCTA, in its current stage, has the potential to be used in clinical practice as a complementary imaging technique in glaucoma management.

Combination of snapshot hyperspectral retinal imaging and optical coherence tomography to identify Alzheimer's disease patients.

INTRODUCTION: The eye offers potential for the diagnosis of Alzheimer's disease (AD) with retinal imaging techniques being explored to quantify amyloid accumulation and aspects of neurodegeneration. To assess these changes, this proof-of-concept study combined hyperspectral imaging and optical coherence tomography to build a classification model to differentiate between AD patients and controls. METHODS: In a memory clinic setting, patients with a diagnosis of clinically probable AD (n = 10) or biomarker-proven AD (n = 7) and controls (n = 22) underwent non-invasive retinal imaging with an easy-to-use hyperspectral snapshot camera that collects information from 16 spectral bands (460-620 nm, 10-nm bandwidth) in one capture. The individuals were also imaged using optical coherence tomography for assessing retinal nerve fiber layer thickness (RNFL). Dedicated image preprocessing analysis was followed by machine learning to discriminate between both groups. RESULTS: Hyperspectral data and retinal nerve fiber layer thickness data were used in a linear discriminant classification model to discriminate between AD patients and controls. Nested leave-one-out cross-validation resulted in a fair accuracy, providing an area under the receiver operating characteristic curve of 0.74 (95% confidence interval [0.60-0.89]). Inner loop results showed that the inclusion of the RNFL features resulted in an improvement of the area under the receiver operating characteristic curve: for the most informative region assessed, the average area under the receiver operating characteristic curve was 0.70 (95% confidence interval [0.55, 0.86]) and 0.79 (95% confidence interval [0.65, 0.93]), respectively. The robust statistics used in this study reduces the risk of overfitting and partly compensates for the limited sample size. CONCLUSIONS: This study in a memory-clinic-based cohort supports the potential of hyperspectral imaging and suggests an added value of combining retinal imaging modalities. Standardization and longitudinal data on fully amyloid-phenotyped cohorts are required to elucidate the relationship between retinal structure and cognitive function and to evaluate the robustness of the classification model.

Microvascular damage assessed by optical coherence tomography angiography for glaucoma diagnosis: a systematic review of the most discriminative regions.

A growing number of studies have reported a link between vascular damage and glaucoma based on optical coherence tomography angiography (OCTA) imaging. This multitude of studies focused on different regions of interest (ROIs) which offers the possibility to draw conclusions on the most discriminative locations to diagnose glaucoma. The objective of this work was to review and analyse the discriminative capacity of vascular density, retrieved from different ROIs, on differentiating healthy subjects from glaucoma patients. PubMed was used to perform a systematic review on the analysis of glaucomatous vascular damage using OCTA. All studies up to 21 April 2019 were considered. The ROIs were analysed by region (macula, optic disc and peripapillary region), layer (superficial and deep capillary plexus, avascular, whole retina, choriocapillaris and choroid) and sector (according to the Garway-Heath map). The area under receiver operator characteristic curve (AUROC) and the statistical difference (p-value) were used to report the importance of each ROI for diagnosing glaucoma. From 96 screened studies, 43 were eligible for this review. Overall, the peripapillary region showed to be the most discriminative region with the highest mean AUROC (0.80 ± 0.09). An improvement of the AUROC from this region is observed when a sectorial analysis is performed, with the highest AUROCs obtained at the inferior and superior sectors of the superficial capillary plexus in the peripapillary region (0.86 ± 0.03 and 0.87 ± 0.10, respectively). The presented work shows that glaucomatous vascular damage can be assessed using OCTA, and its added value as a complementary feature for glaucoma diagnosis depends on the region of interest. A sectorial analysis of the superficial layer at the peripapillary region is preferable for assessing glaucomatous vascular damage.

Depressed mood induction in early cigarette withdrawal is unaffected by acute monoamine precursor supplementation.

BACKGROUND: Cigarette smoking is the leading preventable cause of death; however, quitting is difficult and early relapse is common. Dysphoric mood during early cigarette withdrawal is associated with relapse, and with the exception of bupropion and nortriptyline, few interventions have been developed to prevent this. During early cigarette withdrawal there is an elevation in the levels of monoamine oxidase-A (MAO-A), which removes monoamines excessively and induces oxidative stress and is implicated in creating sad mood. Hence, we conducted a randomized, placebo-controlled, double-blind crossover trial of a dietary supplement designed to counter the effects of elevated MAO-A levels on vulnerability to depressed mood. METHODS: Twenty-one otherwise healthy cigarette smokers completed the protocol, receiving either active dietary supplement followed by washout and placebo or the same in reverse order. The dietary supplement was composed of monoamine precursors (2 g tryptophan, 10 g tyrosine) and blueberry antioxidants (blueberry juice with blueberry extract). Vulnerability to depressed mood was measured by the change in scores of depressed mood on the visual analog scale (VAS) following the sad mood induction paradigm (MIP). RESULTS: There was a significant increase in VAS depressed mood scores after the sad MIP during supplement and placebo, but no difference between active and placebo conditions. There was also a significant increase in urge-to-smoke scores after sad MIP during supplement and placebo but no difference between active and placebo conditions. Reliability of the increase in VAS after MIP was very good. CONCLUSION: The dietary supplement had negligible effect on depressed mood, but sad MIP is a very reliable method that can be applied in future studies to assess other interventions for preventing dysphoric mood during early cigarette withdrawal.

The effect of ethnicity and immigration on treatment resistance in schizophrenia.

BACKGROUND: Treatment resistance is a common issue among schizophrenia patients undergoing antipsychotic treatment. According to the American Psychiatric Association (APA) guidelines, treatment-resistant status is defined as little or no symptom reduction to at least two antipsychotics at a therapeutic dose for a trial of at least six weeks. The aim of the current study is to determine whether ethnicity and migration are associated with treatment resistance. METHODS: In a sample of 251 participants with schizophrenia spectrum disorders, we conducted cross-sectional assessments to collect information regarding self-identified ethnicity, immigration and treatment history. Ancestry was identified using 292 markers overlapping with the HapMap project. Using a regression analysis, we tested whether a history of migration, ethnicity or genetic ancestry were predictive of treatment resistance. RESULTS: Our logistic regression model revealed no significant association between immigration (OR = 0.04; 95%CI = 0.35-3.07; p = 0.93) and treatment resistant schizophrenia. White Europeans did not show significant association with resistance status regardless of whether ethnicity was determined by self-report (OR = 1.89; 95%CI = 0.89-4.20; p = 0.105) or genetic analysis (OR = -0.73; 95%CI = -0.18-2.97; p = 0.667). CONCLUSION: Neither ethnicity nor migrant status was significantly associated with treatment resistance in this Canadian study. However, these conclusions are limited by the small sample size of our investigation.

Non-invasive brain stimulation for negative symptoms in schizophrenia: An updated systematic review and meta-analysis.

BACKGROUND: Schizophrenia is a mental disorder with significant socioeconomic burden. Although current pharmacological treatments are effective for treating positive symptoms, medications have little-to-no effect in the treatment of negative symptoms. OBJECTIVE: To assess the efficacy of non-invasive brain stimulation (NIBS) for negative symptoms in schizophrenia in randomized clinical trials (RCTs). METHODS: A systematic review in Medline and Cochrane Library databases was performed up to May 31, 2017. The primary outcome was Hedges' g for continuous scores in a random-effects model. Heterogeneity was evaluated with the I2 and χ2 tests. Publication bias was assessed using Begg's funnel plot. RESULTS: 31 RCTs (n = 1272) were included, most with small-to-modest sample sizes. Both repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) were superior to sham (Hedges' g = 0.19; 95% CI 0.07-0.32; and 0.5; 0.02-0.97, respectively). Only one study evaluated the use of transcutaneous auricular vagus nerve stimulation (taVNS). The funnel plot and Eggers test showed that the risk of publication bias was low. In relation to heterogeneity, we found an I2 of 0% (p = 0.749) and 51.3% (0.055) for rTMS and tDCS, respectively. CONCLUSION: Both rTMS and tDCS were superior to sham stimulation for ameliorating negative symptoms in schizophrenia. We found no considerable heterogeneity or publication bias in our analysis, corroborating the strength of our findings. Not enough studies on other NIBS techniques, such as taVNS, were found for an isolated analysis. Further RCTs with larger sample sizes are needed to clarify the specific impact of NIBS on negative symptoms in schizophrenia.

Effects of repetitive transcranial magnetic stimulation over supplementary motor area in patients with schizophrenia with obsessive-compulsive-symptoms: A pilot study.

In patients with schizophrenia, obsessive-compulsive symptoms (OCS) are associated with lower rates of quality of life and polypharmacy. No previous controlled studies have tested the efficacy of repetitive transcranial magnetic stimulation (rTMS) on the treatment of OCS in this population. The present study examined the therapeutic effects of rTMS applied to the supplementary motor area (1Hz, 20min, 20 sessions) on OCS and general symptoms in patients with schizophrenia or schizoaffective disorder, and whether this intervention can produce changes in plasma levels of brain derived neurotrophic factor (BDNF). A double-blind randomized controlled trial was conducted. Active and sham rTMS were delivered to 12 patients (6 on each group). Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Brief Psychiatric Rating Scale (BPRS) scores, as well as BDNF levels, were assessed before, after, and 4 weeks after treatment. rTMS did not significantly change the outcomes after treatment and on the follow-up (Y-BOCS: Wald's X(2)=3.172; p=0.205; BPRS: X(2)=1.629; p=0.443; BDNF: X(2)=2.930; p=0.231). There seemed to be a trend towards improvement of BPRS scores 4 weeks after rTMS treatment comparing with sham (Cohen's d=0.875, with 32.9% statistical power). No side effects were reported. Future studies with larger sample sizes are needed.

Clozapine potentiation of GABA mediated cortical inhibition in treatment resistant schizophrenia.

BACKGROUND: Cortical inhibition (CI) deficits have been demonstrated in schizophrenia using transcranial magnetic stimulation (TMS). These CI deficits may be related to decreased GABA activity which may be involved in schizophrenia pathophysiology. Previous cross-sectional studies have also demonstrated greater CI in patients treated with clozapine than other typical/atypical antipsychotics. However, it is not clear if these differences in CI are a result of treatment-resistant illness which necessitates clozapine or are related to clozapine treatment. METHODS: TMS measures of CI (i.e., cortical silent period (CSP) and short-interval cortical inhibition (SICI)) were measured over the motor cortex in 16 patients with schizophrenia before starting clozapine, then 6 weeks and 6 months after starting clozapine. RESULTS: CSP was significantly longer after 6 weeks of treatment with clozapine (p=0.014). From 6 weeks to 6 months, there was no significant difference in CSP (p>0.05). Short-interval cortical inhibition (SICI) was not significantly different at any time after treatment with clozapine (p>0.05). CONCLUSIONS: This prospective-longitudinal study demonstrates that treatment with clozapine is associated with an increase in GABAB mediated inhibitory neurotransmission. Potentiation of GABAB may be a novel neurotransmitter mechanism that is involved in the pathophysiology and treatment of schizophrenia.

The acute effects of exercise on cortical excitation and psychosocial outcomes in men treated for prostate cancer: a randomized controlled trial.

PURPOSE: Regular exercise improves psychological well-being in men treated for prostate cancer (PCa). For this population and among cancer survivors in general, the effect of a single bout of exercise on self-report or objective measures of psychological well-being has not been examined. We examined the acute effect of a single bout of exercise on the cortical silent period (CSP) and on self-reported mood in men that have received treatment for PCa. METHODS: Thirty-six PCa survivors were randomly assigned to 60 min of low to moderate intensity exercise or to a control condition. Outcomes were assessed immediately before and after either the exercise or the control condition. RESULTS: No significant between-group differences were observed in CSP or mood were observed following the exercise session or control conditions. Participants with higher scores of trait anxiety had significantly shorter CSP at baseline, as well as those receiving androgen deprivation therapy. Age and baseline CSP had a low-moderate, but significant negative correlation. Changes in CSP following the exercise condition were strongly negatively correlated with changes in self-reported vigor. CONCLUSION: While we did not observe any acute effect of exercise on the CSP in this population, the associations between CSP and trait anxiety, age, and vigor are novel findings requiring further examination. IMPLICATIONS FOR CANCER SURVIVORS: Exercise did not acutely affect our participants in measures of psychological well-being. Additional mechanisms to explain the chronic psychosocial benefits of exercise previously observed in men with PCa require further exploration. Clinicaltrials.gov Identifier: NCT01715064 (http://clinicaltrials.gov/show/NCT01715064).

Determining optimal rTMS parameters through changes in cortical inhibition.

OBJECTIVES: Evidence shows that repetitive transcranial magnetic stimulation (rTMS) changes cortical inhibition (CI) and excitability and that these changes may relate to its therapeutic effects. This study aimed to investigate the effects of differing durations or 'doses' of rTMS on cortical inhibition and excitability in healthy subjects. METHODS: Four different experiments were conducted: 1 session of 1200 pulses of 1 or 20 Hz active or sham rTMS; 10 sessions of 1 or 20 Hz active or sham rTMS, 1200 pulses/session; 1 session of 3600 pulses of 1 or 20 Hz active or sham rTMS; 1 session of 6000 pulses of 20 Hz active or sham rTMS. Measures of cortical inhibition and excitability included short-interval intracortical inhibition, long interval cortical inhibition, cortical silent period (CSP), motor evoked potential amplitude, resting motor threshold and intracortical facilitation. RESULTS: Only 6000 pulses of 20 Hz rTMS lead to a significant lengthening of the CSP and therefore potentiation of CI. There were no changes to excitability measures. CONCLUSION: Only high frequency rTMS potentiated CI. Longer treatment durations are required to produce such changes. SIGNIFICANCE: Studies investigating the therapeutic effects of rTMS may benefit from extended dosing with increased number of pulses per session. CSP lengthening may be used to guide treatment response.

Abnormal interhemispheric connectivity in male psychopathic offenders.

BACKGROUND: Psychopathic offenders inevitably violate interpersonal norms and frequently resort to aggressive and criminal behaviour. The affective and cognitive deficits underlying these behaviours have been linked to abnormalities in functional interhemispheric connectivity. However, direct neurophysiological evidence for dysfunctional connectivity in psychopathic offenders is lacking. METHODS: We used transcranial magnetic stimulation combined with electroencephalography to examine interhemispheric connectivity in the dorsolateral and motor cortex in a sample of psychopathic offenders and healthy controls. We also measured intracortical inhibition and facilitation over the left and right motor cortex to investigate the effects of local cortical processes on interhemispheric connectivity. RESULTS: We enrolled 17 psychopathic offenders and 14 controls in our study. Global abnormalities in right to left functional connectivity were observed in psychopathic offenders compared with controls. Furthermore, in contrast to controls, psychopathic offenders showed increased intracortical inhibition in the right, but not the left, hemisphere. LIMITATIONS: The relatively small sample size limited the sensitivity to show that the abnormalities in interhemispheric connectivity were specifically related to the dorsolateral prefrontal cortex in psychopathic offenders. CONCLUSION: To our knowledge, this study provides the first neurophysiological evidence for abnormal interhemispheric connectivity in psychopathic offenders and may further our understanding of the disruptive antisocial behaviour of these offenders.