Schizophrenia.

Schizophrenia, characterised by psychotic symptoms and in many cases social and occupational decline, remains an aetiological and therapeutic challenge. Contrary to popular belief, the disorder is modestly more common in men than in women. Nor is the outcome uniformly poor. A division of symptoms into positive, negative, and disorganisation syndromes is supported by factor analysis. Catatonic symptoms are not specific to schizophrenia and so-called first rank symptoms are no longer considered diagnostically important. Cognitive impairment is now recognised as a further clinical feature of the disorder. Lateral ventricular enlargement and brain volume reductions of around 2% are established findings. Brain functional changes occur in different subregions of the frontal cortex and might ultimately be understandable in terms of disturbed interaction among large-scale brain networks. Neurochemical disturbance, involving dopamine function and glutamatergic N-methyl-D-aspartate receptor function, is supported by indirect and direct evidence. The genetic contribution to schizophrenia is now recognised to be largely polygenic. Birth and early life factors also have an important aetiological role. The mainstay of treatment remains dopamine receptor-blocking drugs; a psychological intervention, cognitive behavioural therapy, has relatively small effects on symptoms. The idea that schizophrenia is better regarded as the extreme end of a continuum of psychotic symptoms is currently influential. Other areas of debate include cannabis and childhood adversity as causative factors, whether there is progressive brain change after onset, and the long-term success of early intervention initiatives.

Do the negative symptoms of schizophrenia reflect reduced responsiveness to reward? Examination using a reward prediction error (RPE) task.

BACKGROUND: A leading theory of the negative symptoms of schizophrenia is that they reflect reduced responsiveness to rewarding stimuli. This proposal has been linked to abnormal (reduced) dopamine function in the disorder, because phasic release of dopamine is known to code for reward prediction error (RPE). Nevertheless, few functional imaging studies have examined if patients with negative symptoms show reduced RPE-associated activations. METHODS: Matched groups of DSM-5 schizophrenia patients with high negative symptom scores (HNS, N = 27) or absent negative symptoms (ANS, N = 27) and healthy controls (HC, N = 30) underwent fMRI scanning while they performed a probabilistic monetary reward task designed to generate a measure of RPE. RESULTS: In the HC, whole-brain analysis revealed that RPE was positively associated with activation in the ventral striatum, the putamen, and areas of the lateral prefrontal cortex and orbitofrontal cortex, among other regions. Group comparison revealed no activation differences between the healthy controls and the ANS patients. However, compared to the ANS patients, the HNS patients showed regions of significantly reduced activation in the left ventrolateral and dorsolateral prefrontal cortex, and in the right lingual and fusiform gyrus. HNS and ANS patients showed no activation differences in ventral striatal or midbrain regions-of-interest (ROIs), but the HNS patients showed reduced activation in a left orbitofrontal cortex ROI. CONCLUSIONS: The findings do not suggest that a generalized reduction of RPE signalling underlies negative symptoms. Instead, they point to a more circumscribed dysfunction in the lateral frontal and possibly the orbitofrontal cortex.

Neural correlates of referential/persecutory delusions in schizophrenia: examination using fMRI and a virtual reality underground travel paradigm.

BACKGROUND: The brain functional correlates of delusions have been relatively little studied. However, a virtual reality paradigm simulating travel on the London Underground has been found to evoke referential ideation in both healthy subjects and patients with schizophrenia, making brain activations in response to such experiences potentially identifiable. METHOD: Ninety patients with schizophrenia/schizoaffective disorder and 28 healthy controls underwent functional magnetic resonance imaging while they viewed virtual reality versions of full and empty Barcelona Metro carriages. RESULTS: Compared to the empty condition, viewing the full carriage was associated with activations in the visual cortex, the cuneus and precuneus/posterior cingulate cortex, the inferior parietal cortex, the angular gyrus and parts of the middle and superior temporal cortex including the temporoparietal junction bilaterally. There were no significant differences in activation between groups. Nor were there activations associated with referentiality or presence of delusions generally in the patient group. However, patients with persecutory delusions showed a cluster of reduced activation compared to those without delusions in a region in the right temporal/occipital cortex. CONCLUSIONS: Performance of the metro task is associated with a widespread pattern of activations, which does not distinguish schizophrenic patients and controls, or show an association with referentiality or delusions in general. However, the finding of a cluster of reduced activation close to the right temporoparietal junction in patients with persecutory delusions specifically is of potential interest, as this region is believed to play a role in social cognition.

A taxonomy of key performance errors for emergency intubation.

STUDY OBJECTIVE: Currently the videographic review of emergency intubations is an unstructured, qualitative process. We created a taxonomy of errors that impede the optimal procedural performance of emergency intubation. METHODS: This was a prospective, observational, study reviewing a convenience sample of deidentified laryngoscopy recordings of emergency department intubations that were qualitatively flagged before the study as demonstrating suboptimal technique. These videos were coded for the presence of 13 predetermined performance errors. Our primary outcome was the incidence of each of these specified errors during emergency intubation. Errors fell into 3 categories: errors of structure recognition during laryngoscope insertion, errors of vallecula manipulation, and errors of device delivery. RESULTS: A total of 100 intubation attempts were reviewed. The most common error was inadequate lifting force with the blade tip in the vallecula which lowered the percent of glottic opening, occurring in 45% of the attempts. The least common performance error was the premature removal of the laryngoscope during bougie placement, occurring in only 9% of the videos. CONCLUSION: We developed a taxonomy of 13 performance errors of laryngoscopy. Further study is warranted to determine how to best incorporate these into emergency airway training and the airway review process.

Autobiographical memory and default mode network function in schizophrenia: an fMRI study.

BACKGROUND: The brain functional correlates of autobiographical recall are well established, but have been little studied in schizophrenia. Additionally, autobiographical memory is one of a small number of cognitive tasks that activates rather than de-activates the default mode network, which has been found to be dysfunctional in this disorder. METHODS: Twenty-seven schizophrenic patients and 30 healthy controls underwent functional magnetic resonance imaging while viewing cue words that evoked autobiographical memories. Control conditions included both non-memory-evoking cues and a low level baseline (cross fixation). RESULTS: Compared to both non-memory evoking cues and low level baseline, autobiographical recall was associated with activation in default mode network regions in the controls including the medial frontal cortex, the posterior cingulate cortex and the hippocampus, as well as other areas. Clusters of de-activation were seen outside the default mode network. There were no activation differences between the schizophrenic patients and the controls, but the patients showed clusters of failure of de-activation in non-default mode network regions. CONCLUSIONS: According to this study, patients with schizophrenia show intact activation of the default mode network and other regions associated with recall of autobiographical memories. The finding of failure of de-activation outside the network suggests that schizophrenia may be associated with a general difficulty in de-activation rather than dysfunction of the default mode network per se.

Evidence for default mode network dysfunction in borderline personality disorder.

BACKGROUND: Although executive and other cognitive deficits have been found in patients with borderline personality disorder (BPD), whether these have brain functional correlates has been little studied. This study aimed to examine patterns of task-related activation and de-activation during the performance of a working memory task in patients with the disorder. METHODS: Sixty-seven DSM-IV BPD patients and 67 healthy controls underwent fMRI during the performance of the n-back task. Linear models were used to obtain maps of within-group activations and areas of differential activation between the groups. RESULTS: On corrected whole-brain analysis, there were no activation differences between the BPD patients and the healthy controls during the main 2-back v. baseline contrast, but reduced activation was seen in the precentral cortex bilaterally and the left inferior parietal cortex in the 2-back v. 1-back contrast. The patients showed failure of de-activation affecting the medial frontal cortex and the precuneus, plus in other areas. The changes did not appear to be attributable to previous history of depression, which was present in nearly half the sample. CONCLUSIONS: In this study, there was some, though limited, evidence for lateral frontal hypoactivation in BPD during the performance of an executive task. BPD also appears to be associated with failure of de-activation in key regions of the default mode network.

Prehospital Naloxone and Emergency Department Adverse Events: A Dose-Dependent Relationship.

BACKGROUND: The purpose of this study was to evaluate prehospital and emergency department (ED) interventions and outcomes of patients who received prehospital naloxone for a suspected opioid overdose. OBJECTIVES: The primary objective was to evaluate if the individual dose, individual route, total dose, number of prehospital naloxone administrations, or occurrence of a prehospital adverse event (AE) were associated with the occurrence of AEs in the ED. Secondary objectives included a subset analysis of patients who received additional naloxone while in the ED, or were admitted to an intensive care or step-down unit (ICU). METHODS: This was a retrospective, observational chart review of adult patients who received prehospital naloxone and were transported by ambulance to a suburban academic tertiary care center between 2014 and 2017. Descriptive, univariate, and multivariate statistics were used, with p < 0.05 indicating significance. RESULTS: There were 513 patients included in the analysis, with a median age of 29 years, and median total prehospital naloxone dose of 2 mg. An increasing number of prehospital naloxone doses, an occurrence of a prehospital AE, and a route of administration other than intranasally for the first dose of prehospital naloxone were significantly associated with an increased likelihood of an ED AE. Patients who received < 2 mg of prehospital naloxone had the least likelihood of being admitted to an ICU, whereas patients who received at least 6 mg had a dramatically increased likelihood of ICU admission. CONCLUSIONS: Our results suggest that an increasing number of prehospital naloxone doses was significantly associated with an increased likelihood of an ED adverse event.

Longitudinal brain functional changes between mania and euthymia in bipolar disorder.

OBJECTIVES: While widespread cortical and subcortical brain functional abnormalities have been found in bipolar disorder, the changes that take place between illness phases and recovery are less clearly documented. Only a small number of longitudinal studies of manic patients, in particular, have been carried out. METHODS: Twenty-six bipolar patients underwent fMRI during performance of the n-back working memory task when manic and again after recovery. Twenty-six matched healthy controls were also scanned on two occasions. Task-related activations and de-activations were examined. RESULTS: When manic, the patients showed clusters of significantly reduced activation in the left dorsolateral prefrontal cortex (DLPFC)/precentral cortex and the parietal cortex/superior precuneus bilaterally. They also showed failure of de-activation in the ventromedial frontal cortex (vmPFC). After recovery, activation in the left DLPFC/precentral cortex and in the bilateral parietal cortex/superior precuneus clusters increased significantly. However, failure of de-activation remained present in the vmPFC. CONCLUSIONS: Recovery from mania is associated with normalization of DLPFC and parietal hypoactivation, but not with vmPFC failure of de-activation, which accordingly appears to represent a trait abnormality in the disorder.

Differential failure to deactivate the default mode network in unipolar and bipolar depression.

OBJECTIVES: Neuroimaging studies have revealed evidence of brain functional abnormalities in bipolar depressive disorder (BDD) and major depressive disorder (MDD). However, few studies to date have compared these two mood disorders directly. METHODS: Matched groups of 26 BDD type I patients, 26 MDD patients and 26 healthy controls underwent functional magnetic resonance imaging (fMRI) while performing the n-back working memory task. A whole-brain ANOVA was used to compare the three groups and clusters of significant difference were examined further using region-of-interest (ROI) analysis. RESULTS: The whole-brain ANOVA revealed a single cluster of significant difference in the medial frontal cortex. The BDD and MDD patients both showed failure to deactivate in this area compared to the controls. The BDD patients showed significantly greater failure of deactivation than the MDD patients, which was not accounted for by differences in severity or chronicity of illness between them. CONCLUSIONS: Failure of deactivation, considered to reflect default mode network dysfunction, is present to a greater extent in bipolar than unipolar depression. The study of this network may be useful in the search for brain markers that distinguish the two disorders.

Structural and functional brain changes in delusional disorder.

BACKGROUND: Delusional disorder has been the subject of very little investigation using brain imaging. AIMS: To examine potential structural and/or functional brain abnormalities in this disorder. METHOD: We used structural imaging (voxel-based morphometry, VBM) and functional imaging (during performance of the n-back task and whole-brain resting connectivity analysis) to examine 22 patients meeting DSM-IV criteria for delusional disorder and 44 matched healthy controls. RESULTS: The patients showed grey matter reductions in the medial frontal/anterior cingulate cortex and bilateral insula on unmodulated (but not on modulated) VBM analysis, failure of de-activation in the medial frontal/anterior cingulate cortex during performance of the n-back task, and decreased resting-state connectivity in the bilateral insula. CONCLUSIONS: The findings provide evidence of brain abnormality in the medial frontal/anterior cingulate cortex and insula in delusional disorder. A role for the former region in the pathogenesis of delusions is consistent with several other lines of evidence.

Brain functional changes across the different phases of bipolar disorder.

BACKGROUND: Little is known about how functional imaging changes in bipolar disorder relate to different phases of the illness. AIMS: To compare cognitive task activation in participants with bipolar disorder examined in different phases of illness. METHOD: Participants with bipolar disorder in mania (n = 38), depression (n = 38) and euthymia (n = 38), as well as healthy controls (n = 38), underwent functional magnetic resonance imaging during performance of the n-back working memory task. Activations and de-activations were compared between the bipolar subgroups and the controls, and among the bipolar subgroups. All participants were also entered into a linear mixed-effects model. RESULTS: Compared with the controls, the mania and depression subgroups, but not the euthymia subgroup, showed reduced activation in the dorsolateral prefrontal cortex, the parietal cortex and other areas. Compared with the euthymia subgroup, the mania and depression subgroups showed hypoactivation in the parietal cortex. All three bipolar subgroups showed failure of de-activation in the ventromedial frontal cortex. Linear mixed-effects modelling revealed a further cluster of reduced activation in the left dorsolateral prefrontal cortex in the patients; this was significantly more marked in the mania than in the euthymia subgroup. CONCLUSIONS: Bipolar disorder is characterised by mood state-dependent hypoactivation in the parietal cortex. Reduced dorsolateral prefrontal activation is a further feature of mania and depression, which may improve partially in euthymia. Failure of de-activation in the medial frontal cortex shows trait-like characteristics.

A study of psychotic symptoms in borderline personality disorder.

Patients with borderline personality disorder (BPD) report psychotic symptoms, but it has been questioned whether they are intrinsic to BPD. Thirty patients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), criteria for BPD were drawn from a specialist personality disorder service. Exclusion criteria included a preexisting clinical diagnosis of nonaffective psychotic disorder. Participants underwent structured psychiatric interview using the Present State Examination (PSE), lifetime version. Approximately 60% of the patients reported psychotic symptoms unrelated to drugs or affective disorder. Auditory hallucinations were the most common symptom (50%), which were persistent in the majority of cases. A fifth of the patients reported delusions, half of whom (three patients) also met DSM-IV criteria for schizophrenia, who were previously undiagnosed. The form of auditory hallucinations was similar to that in schizophrenia; the content was predominantly negative and critical. Persistent auditory hallucinations are intrinsic symptoms of BPD. This may inform current diagnostic criteria and have implications for approaches to treatment, both pharmacological and psychological. The presence of delusions may indicate a comorbid axis I disorder.

Alterations in the volume and shape of the basal ganglia and thalamus in schizophrenia with auditory hallucinations.

Different lines of evidence indicate that the structure and physiology of the basal ganglia and the thalamus is disturbed in schizophrenia. However, it is unknown whether the volume and shape of these subcortical structures are affected in schizophrenia with auditory hallucinations (AH), a core positive symptom of the disorder. We took structural MRI from 63 patients with schizophrenia, including 36 patients with AH and 27 patients who had never experienced AH (NAH), and 51 matched healthy controls. We extracted volumes for the left and right thalamus, globus pallidus, putamen, caudate and nucleus accumbens. Shape analysis was also carried out. When comparing to controls, the volume of the right globus pallidus, thalamus, and putamen, was only affected in AH patients. The volume of the left putamen was also increased in individuals with AH, whereas the left globus pallidus was affected in both groups of patients. The shapes of right and left putamen and thalamus were also affected in both groups. The shape of the left globus pallidus was only altered in patients lacking AH, both in comparison to controls and to cases with AH. Lastly, the general PANSS subscale was correlated with the volume of the right thalamus, and the right and left putamen, in patients with AH. We have found volume and shape alterations of many basal ganglia and thalamus in patients with and without AH, suggesting in some cases a possible relationship between this positive symptom and these morphometric alterations.

Psychometric properties of the Spanish version of the Health of Nation Outcome Scales for schizophrenia patients.

Accessible Summary What is known on the subject? Functioning is one of the most affected areas in schizophrenia. Social, occupational and personal domains are affected, and these deficits are responsible for a major part of the disability associated with the disorder. There are several instruments to measure functioning, but the HoNOS provides a wide assessment of impairment in 12 areas of functioning. What does the paper add to existing knowledge? The Spanish version of the HoNOS shows good properties in terms of reliability and validity for use in schizophrenia patients. Although some authors divide the scale according to proposed underlying dimensions, in schizophrenia this division may not be appropriate. What are the implications for practice? A reliable and easy-to-use measure of impairment in different areas of functioning is useful for optimizing the treatment and rehabilitation of patients with schizophrenia. ABSTRACT: INTRODUCTION: The HoNOS scale was designed for the assessment of psychosocial impairment in various domains. While it is widely used in psychiatric settings, it has not been validated in Spanish for use in patients with schizophrenia. AIM: To examine the psychometric properties of the Spanish version of the HoNOS scale in a sample of schizophrenia patients. METHOD: A total of 194 individuals aged 18 to 65 with schizophrenia spectrum diagnoses were evaluated using the HoNOS. Illness severity and level of functioning were also assessed. RESULTS: The HoNOS showed moderate internal consistency, good inter-observer reliability and good test-retest reliability. Factor analysis revealed an internal structure consisting of four factors, with item distribution differing from the theoretical dimensions proposed for the original scale. DISCUSSION: The Spanish version of the HoNOS scale is a reliable and valid instrument for assessing psychosocial impairment in individuals diagnosed with schizophrenia spectrum disorders. However, further research is needed to determine its internal structure more accurately. IMPLICATIONS FOR PRACTICE: The HoNOS scale provides researchers and clinicians with a valid measure of impairment in twelve different domains, which can facilitate and guide the treatment of schizophrenia patients.

Cortical volume abnormalities in schizophrenia: Correlations with symptoms and cognitive impairment.

BACKGROUND: Schizophrenic symptoms are known to segregate into reality distortion, negative and disorganization syndromes, but the correlates of these syndromes with regional brain structural change are not well established. Cognitive impairment is a further clinical feature of schizophrenia, whose brain structural correlates are the subject of conflicting findings. METHODS: 165 patients with schizophrenia were rated for symptoms using the PANSS, and cognitive impairment was indexed by estimated premorbid-current IQ discrepancy. Cortical volume was measured using surface-based morphometry in the patients and in 50 healthy controls. Correlations between clinical and cognitive measures and cortical volume were examined using whole-brain FreeSurfer tools. RESULTS: No clusters of volume reduction were seen associated with reality distortion or disorganization. Negative symptom scores showed a significant inverse correlation with volume in a small cluster in the left medial orbitofrontal gyrus. Larger estimated premorbid-current IQ discrepancies were associated with clusters of reduced cortical volume in the left precentral gyrus and the left temporal lobe. The cluster of association with negative symptoms disappeared when estimated premorbid-current IQ discrepancy was controlled for. CONCLUSIONS: This study does not provide support for an association between brain structural abnormality and reality distortion or disorganization syndromes in schizophrenia. The cluster of volume reduction found in the left medial orbitofrontal cortex correlated with negative symptoms may have reflected the association between this class of symptoms and cognitive impairment. The study adds to existing findings of an association between cognitive impairment and brain structural changes in the disorder.

Structural brain changes associated with tardive dyskinesia in schizophrenia.

BACKGROUND: The pathological basis of tardive dyskinesia is unknown. Although its clinical features implicate the basal ganglia, imaging studies have not found clear evidence that it is associated with volume changes in these or other brain structures. AIMS: To determine, using voxel-based structural imaging, whether there are regions of grey matter volume change in people with schizophrenia who also have tardive dyskinesia compared with those without tardive dyskinesia. METHOD: A total of 81 people with chronic schizophrenia, 32 with tardive dyskinesia and 49 without, were examined using magnetic resonance imaging (MRI) and whole-brain, optimised voxel-based morphometry. A comparison group of 61 healthy controls was also examined. RESULTS: Compared with those without tardive dyskinesia, patients with tardive dyskinesia showed a pattern of volume reductions in predominantly subcortical regions, including the basal ganglia and the thalamus. Within the basal ganglia, volume reductions were seen in the caudate nucleus, to a lesser extent in the putamen, and only marginally in the globus pallidus. The patients with tardive dyskinesia, but not those without, showed significant volume reductions in the basal ganglia compared with the healthy controls but both groups had smaller volumes than controls in other affected areas. CONCLUSIONS: The pathological process or processes that underlie the development of tardive dyskinesia are not just neurochemical in nature, but affect brain structure.

EMDR therapy modulates the default mode network in a subsyndromal, traumatized bipolar patient.

BACKGROUND: Some functional imaging abnormalities found in bipolar disorder are state related, whereas others persist into euthymia. It is uncertain to what extent these latter changes may reflect continuing subsyndromal affective fluctuations and whether those can be modulated by therapeutic interventions. METHOD: We report functional magnetic resonance imaging (fMRI) findings during performance of the n-back working memory task in a bipolar patient who showed a marked improvement in subsyndromal affective symptoms after receiving eye movement desensitization and reprocessing (EMDR) therapy in the context of a clinical trial. RESULTS: The patient's clinical improvement was accompanied by marked changes in functional imaging, as compared to 30 healthy subjects. fMRI changes were noted particularly in deactivation, with failure of deactivation in the medial frontal cortex partially normalizing after treatment. CONCLUSIONS: This case supports the potential therapeutic overall benefit of EMDR in traumatized bipolar patients and suggests a possible neurobiological mechanism of action: normalization of default mode network dysfunction.

Failure of deactivation in bipolar disorder during performance of an fMRI adapted version of the Stroop task.

INTRODUCTION: Few studies have examined the functional brain correlates of the performance of the Stroop task in bipolar disorder (BD). It is also not known whether it is associated with failure of de-activation in the default mode network, as has been found in studies using other tasks. METHODS: Twenty-four BD patients and 48 age, sex and educationally estimated intellectual quotient (IQ) matched healthy subjects (HS) underwent a functional MRI during performance of the counting Stroop task. Task-related activations (incongruent versus congruent condition) and de-activations (incongruent versus fixation) were examined using whole-brain, voxel-based methodology. RESULTS: Both the BD patients and the HS showed activation in a cluster encompassing the left dorsolateral and ventrolateral prefrontal cortex and the rostral anterior cingulate cortex and supplementary motor area, with no differences between them. The BD patients, however, showed significant failure of de-activation in the medial frontal cortex and the posterior cingulate cortex/precuneus. CONCLUSIONS: The failure to find activation differences between BD patients and controls suggests that the 'regulative' component of cognitive control remains intact in the disorder, at least outside episodes of illness. The failure of de-activation found adds to evidence documenting trait-like default mode network dysfunction in the disorder.

Fingerprints as Predictors of Schizophrenia: A Deep Learning Study.

BACKGROUND AND HYPOTHESIS: The existing developmental bond between fingerprint generation and growth of the central nervous system points to a potential use of fingerprints as risk markers in schizophrenia. However, the high complexity of fingerprints geometrical patterns may require flexible algorithms capable of characterizing such complexity. STUDY DESIGN: Based on an initial sample of scanned fingerprints from 612 patients with a diagnosis of non-affective psychosis and 844 healthy subjects, we have built deep learning classification algorithms based on convolutional neural networks. Previously, the general architecture of the network was chosen from exploratory fittings carried out with an independent fingerprint dataset from the National Institute of Standards and Technology. The network architecture was then applied for building classification algorithms (patients vs controls) based on single fingers and multi-input models. Unbiased estimates of classification accuracy were obtained by applying a 5-fold cross-validation scheme. STUDY RESULTS: The highest level of accuracy from networks based on single fingers was achieved by the right thumb network (weighted validation accuracy = 68%), while the highest accuracy from the multi-input models was attained by the model that simultaneously used images from the left thumb, index and middle fingers (weighted validation accuracy = 70%). CONCLUSION: Although fitted models were based on data from patients with a well established diagnosis, since fingerprints remain lifelong stable after birth, our results imply that fingerprints may be applied as early predictors of psychosis. Specially, if they are used in high prevalence subpopulations such as those of individuals at high risk for psychosis.