Trajectories of improvement with repetitive transcranial magnetic stimulation for treatment-resistant major depression in the BRIGhTMIND trial.

Repetitive transcranial magnetic stimulation (rTMS) is an established non-invasive brain stimulation treatment for major depressive disorder, but there is marked inter-individual variability in response. Using latent class growth analysis with session-by-session patient global impression ratings from the recently completed BRIGhTMIND trial, we identified five distinct classes of improvement trajectory during a 20-session treatment course. This included a substantial class of patients noticing delayed onset of improvement. Contrary to prior expectations, members of a class characterised by early and continued improvement showed greatest inter-session variability in stimulated location. By relating target locations and inter-session variability to a well-studied atlas, we estimated an average of 3.0 brain networks were stimulated across the treatment course in this group, compared to 1.1 in a group that reported symptom worsening (p < 0.001, d = 0.893). If confirmed, this would suggest that deliberate targeting of multiple brain networks could be beneficial to rTMS outcomes.

Magnetic resonance imaging connectivity features associated with response to transcranial magnetic stimulation in major depressive disorder.

Transcranial magnetic stimulation (TMS) is an FDA-approved neuromodulation treatment for major depressive disorder (MDD), thought to work by altering dysfunctional brain connectivity pathways, or by indirectly modulating the activity of subcortical brain regions. Clinical response to TMS remains highly variable, highlighting the need for baseline predictors of response and for understanding brain changes associated with response. This systematic review examined brain connectivity features, and changes in connectivity features, associated with clinical improvement following TMS in MDD. Forty-one studies met inclusion criteria, including 1097 people with MDD. Most studies delivered one of two types of TMS to left dorsolateral prefrontal cortex and measured connectivity using resting-state functional MRI. The subgenual anterior cingulate cortex was the most well-studied brain region, particularly its connectivity with the TMS target or with the "executive control network" of brain regions. There was marked heterogeneity in findings. There is a need for greater understanding of how cortical TMS modulates connectivity with, and the activity of, subcortical regions, and how these effects change within and across treatment sessions.

Resting-state functional connectivity correlates of anxiety co-morbidity in major depressive disorder.

Major depressive disorder (MDD) is frequently co-morbid with anxiety disorders. The co-morbid state has poorer functional outcomes and greater resistance to first line treatments, highlighting the need for novel treatment targets. This systematic review examined differences in resting-state brain connectivity associated with anxiety comorbidity in young- and middle-aged adults with MDD, with the aim of identifying novel targets for neuromodulation treatments, as these treatments are thought to work partly by altering dysfunctional connectivity pathways. Twenty-one studies met inclusion criteria, including a total of 1292 people with MDD. Only two studies included people with MDD and formally diagnosed co-morbid anxiety disorders; the remainder included people with MDD with dimensional anxiety measurement. The quality of most studies was judged as fair. Results were heterogeneous, partly due to a focus on a small set of connectivity relationships within individual studies. There was evidence for dysconnectivity between the amygdala and other brain networks in co-morbid anxiety, and an indication that abnormalities of default mode network connectivity may play an underappreciated role in this condition.

Dynamic cerebral reorganization in the pathophysiology of schizophrenia: a MRI-derived cortical thickness study.

BACKGROUND: A structural neuroanatomical change indicating a reduction in brain tissue is a notable feature of schizophrenia. Several pathophysiological processes such as aberrant cortical maturation, progressive tissue loss and compensatory tissue increase could contribute to the structural changes seen in schizophrenia. METHOD: We studied cortical thickness using surface-based morphometry in 98 clinically stable patients with schizophrenia and 83 controls. Using a pattern classification approach, we studied whether the features that discriminate patients from controls vary across the different stages of the illness. Using a covariance analysis, we also investigated if concurrent increases accompany decreases in cortical thickness. RESULTS: Very high levels of accuracy (96.3%), specificity (98.8%) and sensitivity (88%) were noted when classifying patients with <2 years of illness from controls. Within the patient group, reduced thickness was consistently accompanied by increased thickness in distributed brain regions. A pattern of cortical amelioration or normalization (i.e. reduced deviation from controls) was noted with increasing illness duration. While temporo-limbic and fronto-parietal regions showed reduced thickness, the occipital cortex showed increased thickness, especially in those with a long-standing illness. CONCLUSION: A compensatory remodelling process might contribute to the cortical thickness variations in different stages of schizophrenia. Subtle cerebral reorganization reflecting the inherent plasticity of brain may occur concomitantly with processes contributing to tissue reduction in adult patients with schizophrenia.

Shared white-matter dysconnectivity in schizophrenia and bipolar disorder with psychosis.

BACKGROUND: There is an appreciable overlap in the clinical presentation, epidemiology and treatment response of the two major psychotic disorders - schizophrenia and bipolar disorder. Nevertheless, the shared neurobiological correlates of these two disorders are still elusive. Using diffusion tensor imaging (DTI), we sought to identify brain regions which share altered white-matter connectivity across a clinical spectrum of psychotic disorders. METHOD: A sample of 41 healthy controls, 62 patients in a clinically stable state of an established psychotic disorder (40 with schizophrenia, 22 with bipolar disorder) were studied using DTI. Tract-based spatial statistics (TBSS) was used in order to study group differences between patients with psychosis and healthy controls using fractional anisotropy (FA). Probabilistic tractography was used in order to visualize the clusters that showed significant differences between these two groups. RESULTS: The TBSS analysis revealed five clusters (callosal, posterior thalamic/optic, paralimbic, fronto-occipital) with reduced FA in psychosis. This reduction in FA was associated with an increase in radial diffusivity and a decrease in mode of anisotropy. Factor analysis revealed a single white-matter integrity factor that predicted social and occupational functioning scores in patients irrespective of the diagnostic categorization. CONCLUSIONS: Our results show that a shared white-matter dysconnectivity links the two major psychotic disorders. These microstructural abnormalities predict functional outcome better than symptom-based diagnostic boundaries during a clinically stable phase of illness, highlighting the importance of seeking shared neurobiological factors that underlie the clinical spectrum of psychosis.

Biological vulnerability to depression: linked structural and functional brain network findings.

BACKGROUND: Patients in recovery following episodes of major depressive disorder (MDD) remain highly vulnerable to future recurrence. Although psychological determinants of this risk are well established, little is known about associated biological mechanisms. Recent work has implicated the default mode network (DMN) in this vulnerability but specific hypotheses remain untested within the high risk, recovered state of MDD. AIMS: To test the hypothesis that there is excessive DMN functional connectivity during task performance within recovered-state MDD and to test for connected DMN cortical gyrification abnormalities. METHOD: A multimodal structural and functional magnetic resonance imaging (fMRI) study, including task-based functional connectivity and cortical folding analysis, comparing 20 recovered-state patients with MDD with 20 matched healthy controls. RESULTS: The MDD group showed significant task-based DMN hyperconnectivity, associated with hypogyrification of key DMN regions (bilateral precuneus). CONCLUSIONS: This is the first evidence of connected structural and functional DMN abnormalities in recovered-state MDD, supporting recent hypotheses on biological-level vulnerability.

Gyrification of Broca's region is anomalously lateralized at onset of schizophrenia in adolescence and regresses at 2 year follow-up.

Gyrification of the human cerebral cortex starts in the foetus and progresses in early infancy; the pattern of folding in later life provides a lead to early developmental aberration. By studying gyrification at illness onset in adolescence we hoped to clarify the pathophysiology of schizophrenia. Here we find 1) an area of hypergyria includes Broca's area and extends into the Sylvian fissure to encroach on the anterior insula in the left hemisphere, and 2) an area of hypogyria in the superior temporal lobe approximates to Wernicke's area but is located in the right hemisphere and encroaches on the posterior insula. In Broca's/anterior insula area, right lateralization was present in healthy controls but patients were left lateralized: at two year follow-up gyrification had decreased in patients while it increased in controls, and the reduction predicted impaired category fluency. Progressive change was unaccompanied by cortical thinning (investigated only in the brain regions showing baseline changes in gyrification) indicating that the disease process affecting these brain regions (insula, inferior frontal and superior temporal) is not primarily degenerative. A deviation in the lateralized development of peri-Sylvian areas for language production and comprehension appears critical to the pathophysiology of schizophrenia and may point to its species-specific origin.

Surface anatomical profile of the cerebral cortex in obsessive-compulsive disorder: a study of cortical thickness, folding and surface area.

BACKGROUND: Studying the distribution of anatomical abnormalities over the entire cortical surface can help to identify key neural circuits implicated in generating symptoms of neuropsychiatric disorders. There is a significant inconsistency among studies investigating the neuroanatomy of obsessive-compulsive disorder (OCD) because of the confounding influence of co-morbid depression and medication use and the lack of unbiased estimation of whole-brain morphometric changes. It is also unknown whether the distinct surface anatomical properties of thickness, surface area and gyrification, which collectively contribute to grey matter volume (GMV), are independently affected in OCD. Method The cortical maps of thickness, gyrification and surface areal change were acquired from 23 unmedicated OCD patients and 20 healthy controls using an unbiased whole-brain surface-based morphometric (SBM) method to detect regional changes in OCD. Subcortical structures were not assessed in this study. RESULTS: Patients showed a significant increase in the right inferior parietal cortical thickness. Significant increases in gyrification were also noted in the left insula, left middle frontal and left lateral occipital regions extending to the precuneus and right supramarginal gyrus in OCD. Areal contraction/expansion maps revealed no significant regional differences between the patients and controls. In patients, gyrification of the insula significantly predicted the symptom severity measured using Yale-Brown Obsessive-Compulsive Scale (YBOCS). CONCLUSIONS: An alteration in the cortical surface anatomy is an important feature of OCD seen in unmedicated samples that relates to the severity of the illness. The results underscore the presence of a neurodevelopmental aberration underlying the pathophysiology of OCD.

Inefficient cerebral recruitment as a vulnerability marker for schizophrenia.

BACKGROUND: Patients with schizophrenia and their first-degree relatives exhibit both abnormally diminished and increased neural activation during cognitive tasks. In particular, excessive task-related activity is often observed when tasks are easy, suggesting that inefficient cerebral recruitment may be a marker of vulnerability for schizophrenia. This hypothesis might best be tested using a very easy task, thus avoiding confounding by individual differences in task difficulty. METHOD: Eighteen people with schizophrenia, 18 unaffected full siblings of patients with schizophrenia and 26 healthy controls performed an easy auditory target-detection task in a 3-T magnetic resonance imaging (MRI) scanner. Groups were matched for accuracy on the task. Blood oxygen level-dependent (BOLD) responses to non-target stimuli in participants with vulnerability for schizophrenia (siblings and patients) were compared with those of healthy controls, and those of patients with those of unaffected siblings. BOLD responses to targets were compared with baseline, across groups. RESULTS: Subjects with vulnerability for schizophrenia showed significant hyperactivation to non-targets in brain areas activated by targets in all groups, in addition to reduced deactivation to non-targets in areas suppressed by targets in all groups. Siblings showed greater activation than patients to non-targets in the medial frontal cortex. Patients exhibited significantly longer reaction times (RTs) than unaffected siblings and healthy controls. CONCLUSIONS: Inefficient cerebral recruitment is a vulnerability marker for schizophrenia, marked by reduced suppression of brain areas normally deactivated in response to task stimuli, and increased activation of areas normally activated in response to task stimuli. Moreover, siblings show additional activation in the medial frontal cortex that may be protective.

Prefrontal cortex function in remitted major depressive disorder.

BACKGROUND: Recent models of major depressive disorder (MDD) have proposed the rostral anterior cingulate (rACC) and dorsomedial prefrontal cortex (dmPFC) as nexus sites in the dysfunctional regulation of cognitive-affective state. Limited evidence from remitted-state MDD supports these theories by suggesting that aberrant neural activity proximal to the rACC and the dmPFC may play a role in vulnerability to recurrence/relapse within this disorder. Here we present a targeted analysis assessing functional activity within these two regions of interest (ROIs) for groups with identified vulnerability to MDD: first, remitted, high predicted recurrence-risk patients; and second, patients suffering observed 1-year recurrence. Method Baseline T2* images sensitive to blood oxygen level-dependent (BOLD) contrast were acquired from patients and controls during a Go/No-Go (GNG) task incorporating negative feedback, with 1-year patient follow-up to identify recurrence. BOLD contrast data for error commission (EC) and visual negative feedback (VNF) were used in an ROI analysis based on rACC and dmPFC coordinates from the literature, comparing patients versus controls and recurrence versus non-recurrence versus control groups. RESULTS: Analysis of patients (n = 20) versus controls (n = 20) showed significant right dmPFC [Brodmann area (BA) 9] hypoactivity within the patient group, co-localized during EC and VNF, with additional significant rACC (BA 32) hypoactivity during EC. The results from the follow-up analysis were undermined by small groups and potential confounders but suggested persistent right dmPFC (BA 9) hypoactivity associated with 1-year recurrence. CONCLUSIONS: Convergent hypoactive right dmPFC (BA 9) processing of VNF and EC, possibly impairing adaptive reappraisal of negative experience, was associated most clearly with clinically predicted vulnerability to MDD.

Task induced modulation of neural oscillations in electrophysiological brain networks.

In recent years, one of the most important findings in systems neuroscience has been the identification of large scale distributed brain networks. These networks support healthy brain function and are perturbed in a number of neurological disorders (e.g. schizophrenia). Their study is therefore an important and evolving focus for neuroscience research. The majority of network studies are conducted using functional magnetic resonance imaging (fMRI) which relies on changes in blood oxygenation induced by neural activity. However recently, a small number of studies have begun to elucidate the electrical origin of fMRI networks by searching for correlations between neural oscillatory signals from spatially separate brain areas in magnetoencephalography (MEG) data. Here we advance this research area. We introduce two methodological extensions to previous independent component analysis (ICA) approaches to MEG network characterisation: 1) we show how to derive pan-spectral networks that combine independent components computed within individual frequency bands. 2) We show how to measure the temporal evolution of each network with millisecond temporal resolution. We apply our approach to ~10h of MEG data recorded in 28 experimental sessions during 3 separate cognitive tasks showing that a number of networks could be identified and were robust across time, task, subject and recording session. Further, we show that neural oscillations in those networks are modulated by memory load, and task relevance. This study furthers recent findings on electrodynamic brain networks and paves the way for future clinical studies in patients in which abnormal connectivity is thought to underlie core symptoms.

The concept of salience network dysfunction in schizophrenia: from neuroimaging observations to therapeutic opportunities.

A large body of neuroimaging literature suggests that distributed regions in the brain form coordinated largescale networks that show reliable patterns of connectivity when observed using either functional or structural magnetic resonance imaging (MRI) methods. Functional activation within these networks provides a robust and reliable representation of dynamic brain states observed during information processing. One such network comprised of anterior frontoinsular cortex (aFI) and anterior cingulate cortex (ACC) is called the Salience Network (SN). SN has been identified as a system that enables the switch between various dynamic brain states. SN dysfunction has been proposed as a mechanistic model for several core symptoms of schizophrenia. In this review, we explore how various risk factors of schizophrenia could operate through the dysfunctional SN to generate symptoms of psychosis. We also consider the putative neurochemical basis for the SN dysfunction in schizophrenia, and suggest that the SN dysfunction is a viable therapeutic target for a combined pharmacological and cognitive training treatment approach. This combination approach, termed as Brain Network Modulation, could exploit neuronal plasticity to reverse a key pathophysiological deficit in schizophrenia.

Reality distortion is related to the structure of the salience network in schizophrenia.

BACKGROUND: An intrinsic cerebral network comprising the anterior cingulate and anterior insula (the salience network) is considered to play an important role in salience detection in healthy volunteers. Aberrant salience has been proposed as an important mechanism in the production of psychotic symptoms such as delusions and hallucinations (reality distortion). We investigated whether structural deficits in the salience network are associated with the reality distortion seen in schizophrenia. METHOD: A sample of 57 patients in a clinically stable state of schizophrenia and 41 controls were studied with high-resolution magnetic resonance imaging. RESULTS: Bilateral volume reduction was seen in the anterior cingulate and anterior insula in patients with schizophrenia. Reduced volume in the two left-sided regions of the salience network was significantly correlated with the severity of reality distortion. CONCLUSIONS: These findings suggest that a deficit of grey matter in the salience network leads to an impaired attribution of salience to stimuli that is associated with delusions and hallucinations in schizophrenia.

Autistic spectrum disorder traits in children with attention deficit hyperactivity disorder.

BACKGROUND: Current classification systems do not allow for comorbid diagnoses of attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD). Children with ADHD are often screened for ASD during clinical assessment and when recruited to clinical trials. We predicted that children with ADHD would have more autistic traits than controls and that certain traits would be more prevalent. METHODS: The clinically referred sample consisted of 30 children with ADHD and 30 matched controls aged 9-15 years. Children were screened for ASD traits using the Social Aptitudes Scale (SAS) and the Social Communication Questionnaire (SCQ). RESULTS: We found that ASD traits were significantly higher in children with ADHD than controls. None of the children received a diagnosis of autism or ASD. However, a large proportion (28% using the SCQ and 62% using the SAS) of children with ADHD reached screening thresholds for a predictive diagnosis of ASD. Relative to controls, children with ADHD had significantly higher levels of communication and social deficits, but not repetitive behaviours. CONCLUSION: Further work is needed to establish whether autistic-like communication and social difficulties in children with ADHD are part of the broader ASD phenotype or are specific to ADHD.

Reduced event-related low frequency EEG activity in schizophrenia during an auditory oddball task.

This study examines EEG low frequency characteristics which have been linked to specific cognitive functions such as stimulus encoding and attention during an auditory oddball task in schizophrenia patients and healthy controls. EEG data was recorded from 17 young schizophrenia patients in a stable phase of their illness and 17 healthy controls performing an auditory oddball task. Evoked and induced delta and theta activity, N100, P300 amplitude were computed. Between 200-500 ms after a stimulus was presented, patients displayed significantly reduced P300, less evoked and induced delta and theta activity than controls. We conclude that the well known finding of P300 reduction in schizophrenia can be linked to reductions in delta and theta activity, which are a manifestation of impaired stimulus evaluation, memory retrieval, and a lack of sustained attention.

The genetics of symptom dimensions of schizophrenia: review and meta-analysis.

BACKGROUND: The use of symptom dimensions of schizophrenia as quantitative phenotypes has been proposed as a mean to reduce the heterogeneity of schizophrenia and facilitate genetic research. However, the genetic background of symptom dimensions is not clear. AIM: We aim to investigate whether the symptom dimensions "reality distortion", "psychomotor poverty" and "disorganization" are heritable phenotypes. METHOD: We performed a Medline search including all papers from 1980 to August 2007. In addition to reviewing the articles, we performed meta-analyses on these studies where possible. RESULTS: We identified 18 relevant papers. Only the studies on affected sibling pairs were suitable for meta-analysis. Data from twin and affected sibling studies are consistent with a genetic contribution to the disorganization dimension. However these studies did not unequivocally support a large genetic contribution to neither the reality distortion symptom dimension nor to the psychomotor poverty symptom dimension. In contrast several molecular genetic studies did report associations of genes with psychomotor poverty. CONCLUSIONS: These data suggest that only the disorganization symptom dimension may provide an useful alternative phenotype for genetic research. More research is required to make any definitive conclusions.

Cognitive deficits in early-onset schizophrenia spectrum patients and their non-psychotic siblings: a comparison with ADHD.

BACKGROUND: Previous research has shown cognitive deficits in patients with schizophrenia spectrum disorders in the areas of executive function, verbal memory and attention. Subtle deficits have been shown in healthy first-degree relatives of patients, suggesting that they may be trait markers. The specificity of these markers for schizophrenia compared with another neurodevelopmental disorder, Attention Deficit Hyperactivity Disorder (ADHD) has not been reliably established. METHODS: The Rey Auditory Verbal Learning Test (RAVLT), Hayling Sentence Completion Test (HSCT), FAS Test of orthographic verbal fluency (FAS) and Continuous Performance Test-Identical Pairs (CPT-IP) were administered to adolescent schizophrenia spectrum patients (SZ; n=30), adolescent siblings of schizophrenia spectrum patients (SZ-SIB; n=36), healthy control participants (HC; n=72); a neurodevelopmental comparison group of adolescents with ADHD (n=27). RESULTS: The SZ group were impaired on all measures. The SZ-SIB group were impaired on IQ, immediate recall (RAVLT), target sensitivity (CPT-IP), response initiation (HSCT); error rates for the FAS and HSCT. There were no significant differences between the SZ-SIB and ADHD groups on individual measures of cognitive function. Principal Components Analysis revealed four factors on which further analyses were conducted. The SZ-SIB and ADHD groups showed different profiles of impairment on components related to response initiation and sustained attention/vigilance when each was compared with the HC group. CONCLUSIONS: Deficits in intellectual function, verbal memory and response initiation/inhibition were found in the SZ-SIB group indicating that these are markers of risk for schizophrenia. Subtle differences in profiles of impairment in the SZ-SIB and ADHD groups on composite measures of attention and response initiation require further investigation.

Dysfunction of a distributed neural circuitry in schizophrenia patients during a working-memory performance.

BACKGROUND: In a recent longitudinal study of first-episode schizophrenia patients, we found that while dysfunction of the right dorsolateral prefrontal cortex (DLPFC), right thalamus, left cerebellum and cingulate gyrus normalized with antipsychotic treatment and significant reduction in symptomatology, the left DLPFC, left thalamus, and right cerebellum remained disturbed. In the present study we investigated whether these abnormalities are also present in clinically stable, relatively well-functioning schizophrenia patients in comparison to control subjects during performance of the N-back working-memory task. METHOD: Twelve schizophrenia and 12 control subjects completed the study. The functional images collected during scanning were analyzed using a random-effects model in a restricted set of six regions of interest (ROIs). In addition, the exploratory search in the entire brain volume was performed. RESULTS: The ROI analyses revealed relative underactivation in the region of the left DLPFC and the right cerebellum, as well as overactivation in the left cerebellum. The exploratory whole-brain search exposed additional overactivation in the medial frontal, anterior cingulate, and left parietal cortices. CONCLUSIONS: The present study provides evidence of significant underactivations in stable schizophrenia patients in regions that we have previously observed to be dysfunctional in acutely psychotic and partially remitted patients, together with extensive overactivations in several regions that potentially reflect some compensatory mechanism or increased effort on the working-memory task.

Changes in distributed neural circuitry function in patients with first-episode schizophrenia.

BACKGROUND: A number of functional brain abnormalities have been reported in schizophrenia, but it remains to be determined which of them represent trait and state markers of the illness. AIMS: To delineate regional brain dysfunctions that remain stable and those that fluctuate during the course of schizophrenia. METHOD: A cohort of patients with first-episode schizophrenia and a matched group of control participants underwent functional magnetic resonance imaging on two occasions 6-8 weeks apart during performance of a working memory task. The patients' disease was in partial remission at the second scan. RESULTS: Relative to control participants, the function of the left dorsolateral prefrontal cortex, left thalamus and right cerebellum remained disturbed in the people with schizophrenia, whereas the dysfunction of the right dorsolateral prefrontal cortex, right thalamus, left cerebellum and cingulate gyrus normalised, with significant reduction in symptoms. CONCLUSIONS: These results suggest that dysfunction of the left fronto-thalamo-cerebellar circuitry is a relatively stable characteristic of schizophrenia, whereas disturbance of the right circuitry and cingulate gyrusis predominantly a state-related phenomenon.

Neurological soft signs discriminating mood disorders from first episode schizophrenia.

OBJECTIVE: To investigate the specificity of neurological soft signs (NSS) for first episode schizophrenia compared with mood disorders. METHOD: We assessed NSS in a sample of 60 healthy controls, 191 first episode psychosis patients and 81 mood disorder patients. We used a principle component analysis to identify dimensions of NSS. We subsequently investigated the specificity of these dimensions for schizophrenia and their relationships with medication and symptom scores. RESULTS: We identified five dimensions; coordination disorders, movement disorders, increased reflexes, dyskinesia and catatonia. These dimensions were related to neural circuits associated with schizophrenia and mood disorders and included the fronto-striatal-thalamic and the fronto-cerebellar pathway. The movement disorder dimension, which was suggestive for the involvement of the fronto-striatal-thalamic pathway, was specific for first episode schizophrenia independent from medication. CONCLUSION: NSS are the result of circuitry dysfunctions rather than overall dysfunction and a particular set of NSS shows specificity for schizophrenia.