Schizophrenia syndrome due to C9ORF72 mutation case report: a cautionary tale and role of hybrid brain imaging!

BACKGROUND: Frontal variant frontotemporal dementia is a common cause of presenile dementia. A hexanucleotide expansion on chromosome 9 has recently been recognized as the most common genetic mutation cause of this illness. This sub-type tends to present psychiatrically with psychosis being a common presenting symptom before the onset of cognitive changes or brain atrophy. A few case series have been published describing the prominence of early psychotic symptoms, and lack of clear brain atrophy on clinical brain imaging imposing a challenge in reaching early accurate diagnosis. In this report, we present a case whereby the diagnosis of Schizophrenia syndrome was made and the patient was treated for years with multiple interventions for that syndrome before reaching the accurate diagnosis of Frontal variant frontotemporal dementia due to hexanucleotide expansion on chromosome 9. This diagnosis was confirmed after genetic testing and findings on a hybrid Positron Emission Tomography/Magnetic Resonance Imaging scanning. A 60-year-old female diagnosed with schizophrenia at age 50 after presenting with delusions and hallucinations, which proved to be refractor to several lines of pharmacological and non-pharmacological interventions including electroconvulsive therapy. Patient had a history of post-partum psychosis in her 20s. She was referred to cognitive neurology due to progressive decline in function. While clinical structural brain imaging data were not adequate to support an alternative neurological diagnosis, careful inquiry elicited a history of psychotic illness followed by progressive decline in a sister. Genetic testing confirmed hexanucleotide expansion on chromosome 9 mutation. The patient was offered a state-of-the-art FD-Glucose Positron Emission Tomography/Magnetic Resonance Imaging scan available at our centre. While volumetric Magnetic Resonance Imaging scan did not show volume loss in frontotemporal areas, the hybrid scan showed regionally specific deficit in FD-Glucose Positron Emission Tomography affecting medial superior frontal, insula, inferior temporal, thalamus, and anterior cingulate cortex consistent with behavioral variant frontotemporal dementia. CONCLUSIONS: This case highlights the importance of considering Frontal variant frontotemporal dementia due to hexanucleotide expansion on chromosome 9 when facing relatively late-onset, refractory schizophrenia-like syndrome. Careful history from all available sources to elicit family history of similar presentation is very important. Genetic testing and functional brain imaging can aid in confirming the diagnosis and potentially streamlining the management of these cases.

Baseline effective connectivity predicts response to repetitive transcranial magnetic stimulation in patients with treatment-resistant depression.

Repetitive transcranial magnetic stimulation (rTMS) has become a popular treatment option for treatment-resistant depression (TRD). However, suboptimal response rates highlight the need for improved efficacy through optimisation of treatment protocol and patient selection. We investigate whether the limbic salience network and its connectivity with prefrontal stimulation sites predict immediate and longer-term responsiveness to rTMS. Twenty-seven patients with TRD were randomly allocated to receive 16 sessions of either conventional rTMS or intermittent theta-burst (iTBS) over 4 weeks; delivered using connectivity profiling and neuronavigation to target person-specific dorsolateral prefrontal cortex (DLPFC). At baseline and 3-month follow-up, patients underwent clinical assessment and scanning session, and 1-month clinical follow-up. Resting-state fMRI data were entered into seed-based functional and effective connectivity analyses between right anterior insula (rAI) and DLPFC target, and independent components analysis to extract resting-state networks. Cerebral blood flow (CBF) was also assessed in the rAI. All brain measures were compared between baseline and follow-up, and related to treatment response at 1- and 3-months. Baseline fronto-insular effective connectivity and salience network connectivity were significantly positively correlated, while baseline rAI CBF was negatively correlated, with early (1-month) response to rTMS treatment but not sustained response (3-months), suggesting persistence of therapeutic response is not associated with baseline features. Connectivity or CBF measures did not change between the two time points. We demonstrate that fronto-insular and salience-network interactions can predict early response to rTMS in TRD, suggesting that these network nodes may be key regions toward developing rTMS response biomarkers.

Clinical utility of a short resting-state MRI scan in differentiating bipolar from unipolar depression.

OBJECTIVE: Depression in bipolar disorder (BipD) requires a therapeutic approach that is from treating unipolar major depressive disorder (UniD), but to date, no reliable methods could separate these two disorders. The aim of this study was to establish the clinical validity and utility of a non-invasive functional MRI-based method to classify BipD from UniD. METHOD: The degree of connectivity (degree centrality or DC) of every small unit (voxel) with every other unit of the brain was estimated in 22 patients with BipD and 22 age, gender, and depressive severity-matched patients with UniD and 22 healthy controls. Pattern classification analysis was carried out using a support-vector machine (SVM) approach. RESULTS: Degree centrality pattern from 8-min resting fMRI discriminated BipD from UniD with an accuracy of 86% and diagnostic odds ratio of 9.6. DC was reduced in the left insula and increased in bilateral precuneus in BipD when compared to UniD. In this sample with a high degree of uncertainty (50% prior probability), positive predictive value of the DC test was 79%. CONCLUSION: Degree centrality maps are potential candidate measures to separate bipolar depression from unipolar depression. Test performance reported here requires further pragmatic evaluation in regular clinical practice.

Abnormalities in the effective connectivity of visuothalamic circuitry in schizophrenia.

BACKGROUND: Sensory-processing deficits appear crucial to the clinical expression of symptoms of schizophrenia. The visual cortex displays both dysconnectivity and aberrant spontaneous activity in patients with persistent symptoms and cognitive deficits. In this paper, we examine visual cortex in the context of the remerging notion of thalamic dysfunction in schizophrenia. We examined specific regional and longer-range abnormalities in sensory and thalamic circuits in schizophrenia, and whether these patterns are strong enough to discriminate symptomatic patients from controls. METHOD: Using publicly available resting fMRI data of 71 controls and 62 schizophrenia patients, we derived conjunction maps of regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFF) to inform further seed-based Granger causality analysis (GCA) to study effective connectivity patterns. ReHo, fALFF and GCA maps were entered into a multiple kernel learning classifier, to determine whether patterns of local and effective connectivity can differentiate controls from patients. RESULTS: Visual cortex shows both ReHo and fALFF reductions in patients. Visuothalamic effective connectivity in patients was significantly reduced. Local connectivity (ReHo) patterns discriminated patients from controls with the highest level of accuracy of 80.32%. CONCLUSIONS: Both the inflow and outflow of Granger causal information between visual cortex and thalamus is affected in schizophrenia; this occurs in conjunction with highly discriminatory but localized dysconnectivity and reduced neural activity within the visual cortex. This may explain the visual-processing deficits that are present despite symptomatic remission in schizophrenia.

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.

Failed cooperative, but not competitive, interaction between large-scale brain networks impairs working memory in schizophrenia.

BACKGROUND: A large-scale network named the default mode network (DMN) dynamically cooperates and competes with an external attention system (EAS) to facilitate various cognitive functioning that is prominently impaired in schizophrenia. However, it is unclear whether the cognitive deficit in schizophrenia is related to the disrupted competition and/or cooperation between these two networks. METHOD: A total of 35 schizophrenia patients and 30 healthy controls were scanned using gradient-echo echo-planar imaging during n-back working memory (WM) processing. Brain activities of the DMN and EAS were measured using general linear modelling of the functional magnetic resonance imaging data. Dynamic interaction between the DMN and EAS was decomposed into two directions using Granger causality analysis. RESULTS: We observed a significant failure of DMN suppression in patients with schizophrenia, which was significantly related to WM/attentional deficit. Granger causality modelling showed that in healthy controls, while the EAS inhibitorily influenced the DMN, the DMN exerted an 'excitatory' or cooperative influence back on the EAS, especially in those with lower WM accuracy. In schizophrenia, this 'excitatory' DMN→EAS influence within the reciprocal EAS-DMN loop was significantly reduced, especially in patients with WM/attentional deficit. CONCLUSIONS: The dynamic interaction between the DMN and EAS is likely to be comprised of both competitive and cooperative influences. In healthy controls, both the 'inhibitory' EAS→DMN interaction and 'excitatory' DMN→EAS interaction are correlated with WM performance. In schizophrenia, reduced 'cooperative' influence from the DMN to dorsal nodes of the EAS occurs in the context of non-suppression of the DMN and may form a possible pathophysiological substrate of WM deficit and attention disorder.

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.

Cortical thickness and oscillatory phase resetting: a proposed mechanism of salience network dysfunction in schizophrenia.

Schizophrenia is characterised by both electrophysiological abnormalities and consistent changes in the structure of cortical grey matter. But the relationship between these two observations is largely unknown. Structural changes reported in schizophrenia include reduced grey matter volume, thickness and surface area in several cortical regions, but most frequently in the insula and anterior cingulate cortex. These two regions together constitute an intrinsic brain circuit known as the "Salience Network", which has a key role in stimulus processing. During stimulus processing tasks, evoked activity is noted using electroencephalography (EEG). Phase resetting of ongoing oscillations contributes to this evoked activity. Neuronal oscillations play a crucial role in cerebral recruitment during cognitive tasks, and influencing the oscillatory phase can modulate cortical excitability and the transition between various cognitive states. At a network level, such a transition or switch is thought to be enabled by the Salience Network. In this study, we investigated the relationship between the cortical thickness in the Salience Network (measured using MRI) and the degree of phase resetting observed during an oddball task (measured using EEG) in 18 medicated male patients in a clinically stable phase of schizophrenia and 20 age and gender matched healthy controls. We obtained a measure of partial phase resetting after a stimulus is presented, and a second measure representing mean evoked activity, using the methods proposed by Martinez-Montes. Using MRI analysis, we have firstly shown that there is a significant loss of cortical thickness of regions that constitute the Salience Network in patients with schizophrenia. EEG analysis revealed that in healthy controls, the expected relationship between phase resetting and evoked electrical activity is observed, but in patients with schizophrenia the theta phase resetting is a weak predictor of the activity evoked by attending to a target stimulus, though the difference between the groups did not reach statistical significance in the present sample. Furthermore, in patients with schizophrenia the reduced thickness in the Salience Network is associated with the inefficient phase resetting of theta oscillations. Our findings suggest that the grey matter reduction seen in the Salience Network in patients with schizophrenia has substantial functional consequences. In particular, the structural defect of the insula that is seen in schizophrenia is likely to be associated with less efficient recruitment of brain circuits for processing information. This implies a possible mechanism by which disruptions in the intrinsic Salience Network can result in a general disturbance in salience detection seen in schizophrenia.

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.