A novel way to quantify schizophrenia symptoms in clinical trials.

BACKGROUND: A major problem in quantifying symptoms of schizophrenia is establishing a reliable distinction between enduring and dynamic aspects of psychopathology. This is critical for accurate diagnosis, monitoring and evaluating treatment effects in both clinical practice and trials. MATERIALS AND METHODS: We applied Generalizability Theory, a robust novel method to distinguish between dynamic and stable aspects of schizophrenia symptoms in the widely used Positive and Negative Symptom Scale (PANSS) using a longitudinal measurement design. The sample included 107 patients with chronic schizophrenia assessed using the PANSS at five time points over a 24-week period during a multi-site clinical trial of N-Acetylcysteine as an add-on to maintenance medication for the treatment of chronic schizophrenia. RESULTS: The original PANSS and its three subscales demonstrated good reliability and generalizability of scores (G = 0.77-0.93) across sample population and occasions making them suitable for assessment of psychosis risks and long-lasting change following a treatment, while subscales of the five-factor models appeared less reliable. The most enduring symptoms represented by the PANSS were poor attention, delusions, blunted affect and poor rapport. More dynamic symptoms with 40%-50% of variance explained by patient transient state including grandiosity, preoccupation, somatic concerns, guilt feeling and hallucinatory behaviour. CONCLUSIONS: Identified dynamic symptoms are more amendable to change and should be the primary target of interventions aiming at effectively treating schizophrenia. Separating out the dynamic symptoms would increase assay sensitivity in trials, reduce the signal to noise ratio and increase the potential to detect the effects of novel therapies in clinical trials.

Neurological Soft Signs Predict Auditory Verbal Hallucinations in Patients With Schizophrenia.

Neurological soft signs (NSS) are well documented in individuals with schizophrenia (SZ), yet so far, the relationship between NSS and specific symptom expression is unclear. We studied 76 SZ patients using magnetic resonance imaging (MRI) to determine associations between NSS, positive symptoms, gray matter volume (GMV), and neural activity at rest. SZ patients were hypothesis-driven stratified according to the presence or absence of auditory verbal hallucinations (AVH; n = 34 without vs 42 with AVH) according to the Brief Psychiatric Rating Scale. Structural MRI data were analyzed using voxel-based morphometry, whereas intrinsic neural activity was investigated using regional homogeneity (ReHo) measures. Using ANCOVA, AVH patients showed significantly higher NSS in motor and integrative functions (IF) compared with non-hallucinating (nAVH) patients. Partial correlation revealed that NSS IF were positively associated with AVH symptom severity in AVH patients. Such associations were not confirmed for delusions. In region-of-interest ANCOVAs comprising the left middle and superior temporal gyri, right paracentral lobule, and right inferior parietal lobule (IPL) structure and function, significant differences between AVH and nAVH subgroups were not detected. In a binary logistic regression model, IF scores and right IPL ReHo were significant predictors of AVH. These data suggest significant interrelationships between sensorimotor integration abilities, brain structure and function, and AVH symptom expression.

tDCS for auditory verbal hallucinations in a case of schizophrenia and left frontal lesion: efield simulation and clinical results.

Transcranial direct current stimulation (tDCS) has been explored for treatment of several neuropsychiatric disorders. For tDCS use in structural brain lesions there is some evidence from motor stroke rehabilitation and post-stroke depression. Here we report the application of tDCS in a woman previously diagnosed with schizophrenia presenting refractory auditory verbal hallucinations and left prefrontal tissue lesion. Treatment with 20 left fronto-temporal tDCS had no effect on psychiatric symptoms and neuropsychological evaluation. An ex-post electric field simulation and calculation of dorsolateral prefrontal cortex activation showed lower activation in this patient compared to a matched non-lesioned schizophrenia, and healthy control brain.

A Metabolic Brain Pattern Associated With Anti-N-Methyl-D-Aspartate Receptor Encephalitis.

BACKGROUND: Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis causes substantial neurological disability. Autoantibodies causing encephalitis directed against the neuronal cell surface or synapse are of diagnostic importance giving the possibility of successful immunotherapy. OBJECTIVE: In this study, we aim to provide supporting evidence that brain 18F-FDG-PET may be helpful in identifying likely patterns of regional brain glucose metabolism. METHODS: Thirty-three patients (18 men and 15 women; age range of 17-55 y) with positive NMDA receptor antibody encephalitis that underwent an 18F-FDG-PET imaging examination were prospectively selected and compared with a reference group of 14 brain 18F-FDG-PET scans from healthy volunteers using voxel-based statistical analysis. Clusters of hyper- and hypo-metabolism were reported for the whole sample of patients (FWE-corrected P < 0.05), and uncorrected at P < 0.005 for a group of relapsed patients. RESULTS: Mixed metabolic patterns (focal/bilateral hypermetabolism in the temporal lobe, insula, and cerebellum; associated with severe bilateral hypometabolism in the occipital and parietal lobes) were found. CONCLUSIONS: Our findings suggest that 18F-FDG-PET should be included as an imaging tool when assessing affected patients in the clinical workup to rule out anti-NMDA encephalitis and help determine the most effective treatment.

Functional imaging localization of complex organic hallucinations.

Background: fMRI of mental phenomena is quite difficult to perform because lack of patient's cooperation or because the symptoms are stable. In some exceptional cases, however, fMRI and DTI are capable to provide insights on the anatomy of organic hallucinations. Methods: In this report we describe a 14-year-old boy with a left fronto-dorsal tumor who experienced chronic complex brief, frequent and repetitive complex visual and auditory hallucinations. His clinical picture included multiple and severe social and mood problems. During a presurgical fMRI mapping the patient complained of having the visual and auditory hallucinations. A block-design FMRI paradigm was obtained from the event timecourse. Deterministic DTI of the brain was obtained seeding the lesion as ROI. The patient underwent surgery and electrocorticography of the lesional area. Results: The fMRI of the hallucinations showed activation in the left inferior frontal gyrus (IFG) and the peri-lesional area. The tractography of the tumor revealed structural aberrant connectivity to occipital and temporal areas in addition to the expected connectivity with the IFG via the aslant fasciculus and homotopic contralateral areas. Intraoperative EEG demonstrated epileptic discharges in the tumor and neighboring areas. After resection, the patient's hallucinations stopped completely. He regained his normal social life and recover his normal mood. He remained asymptomatic for 90 days. Afterwards, hallucinations reappeared but with less intensity. Conclusions: To our knowledge, this is the first reported case of combined functional and structural connectivity imaging demonstrating brain regions participating in a network involved in the generation of complex auditory and visual hallucinations.

Epilepsy with auditory features: Long-term outcome and predictors of terminal remission.

OBJECTIVE: To assess the long-term outcome of epilepsy with auditory features (EAF) and to identify the clinical predictors for prognosis. METHODS: The study involved consecutive EAF patients with a follow-up of ≥5 years. Terminal remission (TR) was defined as a period of ≥5 consecutive years of seizure freedom at the last follow-up. We used Kaplan-Meier estimate to calculate the cumulative time-dependent probability of conversion to TR. Log-rank test and multivariate Cox regression analyses were performed to study the association between time to TR and prognostic determinants. RESULTS: We included 123 EAF patients (male/female = 58/65) with a median follow-up of 11 years (1626.9 person-years). Most were sporadic cases (68.3%), whereas 31.7% reported a family history of epilepsy. At last assessment, 42 patients had achieved TR (34.1%). Of the remaining 81 cases with no TR (65.9%), 37% had been in remission for 1-4 years and 62.9% still had seizures within the past year. The cumulative rates of TR were 26.6%, 35.7%, and 51.6% at 10, 20, and 30 years from inclusion. On multivariate analysis, age at onset > 10 years (hazard ratio [HR] = 3.2, P = .028), auditory aura characterized by distortions only versus simple/complex hallucinations (HR = 2.9, P = .041), and unremarkable scalp electroencephalogram (EEG) versus EEG with focal epileptiform activity (HR = 3.5, P = .041) were associated with TR. SIGNIFICANCE: Our data show a wide prognostic spectrum of EAF, ranging from mild forms with spontaneous remission, to severely refractory epilepsy addressed to surgery. The outcome, less favorable than expected from previous studies, appears to be primarily a function of 3 prognostic negative risk factors: age at onset < 10 years, auditory aura characterized by complex auditory hallucinations, and focal epileptiform abnormalities on scalp EEG. These predictors, easy to collect even at the first visit, may inform both clinicians and patients about the long-term prognosis and aid patient management.

Acute Charles Bonnet Syndrome following Hughes procedure.

A 69-year-old male experienced monocular formed visual hallucinations after occlusion of the right eye following resection of eyelid basal cell carcinoma and reconstruction with a Hughes procedure (tarsoconjunctival flap). His symptoms included recurrent, well-defined, organized, complex, formed images of small children playing in the snow. These visual phenomena occurred only in the occluded eye, began several hours after surgery, and recurred intermittently several times daily for 4 days, lasting several minutes with each occurrence. The patient retained insight into the false nature of the images throughout the duration of his symptoms, and the hallucinations resolved spontaneously while the flap was still in place. To our knowledge, this is the first reported case of Charles Bonnet Syndrome (CBS) following a Hughes procedure in a patient with normal visual acuity in the non-occluded fellow eye. Unlike other reported cases of acute onset CBS following transient monocular occlusion, hallucinations in the occluded eye remitted prior to restoration of vision in the occluded eye. Ophthalmologists should be aware of the potential for CBS following even transient monocular occlusion and should consider warning patients about its potential to occur.

Opioid-induced Hallucinations: A Review of the Literature, Pathophysiology, Diagnosis, and Treatment.

Despite their association with multiple adverse effects, opioid prescription continues to increase. Opioid-induced hallucination is an uncommon yet significant adverse effect of opioid treatment. The practitioner may encounter patient reluctance to volunteer the occurrence of this phenomenon because of fears of being judged mentally unsound. The majority of the literature concerning opioid-induced hallucinations arises from treatment during end-of-life care and cancer pain. Because the rate of opioid prescriptions continues to increase in the population, the rate of opioid-associated hallucinations may also conceivably increase. With a forecasted increase in the patient-to-physician ratio, opioid therapy is predicted to be provided by practitioners of varying backgrounds and medical specialties. Hence, knowledge of the pharmacology and potential adverse effects of these agents is required. This review seeks to increase awareness of this potential complication through a discussion of the literature, potential mechanisms of action, diagnosis, and treatment strategies.

Neural correlates of hallucinations in bipolar disorder

Objective: Approximately one-half of all patients affected by bipolar disorder present with psychotic features on at least one occasion. Several studies have found that alterations in the activity of mesolimbic and prefrontal regions are related to aberrant salience in psychotic patients. The aim of the present study was to investigate the structural correlates of a history of hallucinations in a sample of euthymic patients with bipolar I disorder (BD-I). Methods: The sample consisted of 21 euthymic patients with BD-I and no comorbid axis I DSM-IV-TR disorders. Voxel based morphometry (VBM) was used to compare patients with and without a lifetime history of hallucinations. Preprocessing was performed using the Diffeomorphic Anatomical Registration through Exponentiated Lie Algebra (DARTEL) algorithm for VBM in SPM8. Images were processed using optimized VBM. Results: The main finding of the present study was a reduction in gray matter volume in the right posterior insular cortex of patients with BD-I and a lifetime history of hallucinations, as compared to subjects with the same diagnosis but no history of hallucinations. Conclusions: This finding supports the presence of abnormalities in the salience network in BD patients with a lifetime history of hallucinations. These alterations may be associated with an aberrant assignment of salience to the elements of one’s own experience, which could result in psychotic symptoms.

A white matter tract mediating awareness of speech.

OBJECTIVE: To investigate the effects of extraoperative electrical stimulation of fiber tracts connecting the language territories. METHODS: We describe results of extraoperative electrical stimulation of stereotactic electrodes in 3 patients with epilepsy who underwent presurgical evaluation for epilepsy surgery. Contacts of these electrodes sampled, among other structures, the suprainsular white matter of the left hemisphere. RESULTS: Aside from speech disturbance and speech arrest, subcortical electrical stimulation of white matter tracts directly superior to the insula representing the anterior part of the arcuate fascicle, reproducibly induced complex verbal auditory phenomena including (1) hearing one's own voice in the absence of overt speech, and (2) lack of perception of arrest or alteration in ongoing repetition of words. CONCLUSION: These results represent direct evidence that the anterior part of the arcuate fascicle is part of a network that is important in the mediation of speech planning and awareness likely by linking the language areas of the inferior parietal and posterior inferior frontal cortices. More specifically, our observations suggest that this structure may be relevant to the pathophysiology of thought disorders and auditory verbal hallucinations.

Sleep Deprivation Reveals Altered Brain Perfusion Patterns in Somnambulism.

BACKGROUND: Despite its high prevalence, relatively little is known about the pathophysiology of somnambulism. Increasing evidence indicates that somnambulism is associated with functional abnormalities during wakefulness and that sleep deprivation constitutes an important drive that facilitates sleepwalking in predisposed patients. Here, we studied the neural mechanisms associated with somnambulism using Single Photon Emission Computed Tomography (SPECT) with 99mTc-Ethylene Cysteinate Dimer (ECD), during wakefulness and after sleep deprivation. METHODS: Ten adult sleepwalkers and twelve controls with normal sleep were scanned using 99mTc-ECD SPECT in morning wakefulness after a full night of sleep. Eight of the sleepwalkers and nine of the controls were also scanned during wakefulness after a night of total sleep deprivation. Between-group comparisons of regional cerebral blood flow (rCBF) were performed to characterize brain activity patterns during wakefulness in sleepwalkers. RESULTS: During wakefulness following a night of total sleep deprivation, rCBF was decreased bilaterally in the inferior temporal gyrus in sleepwalkers compared to controls. CONCLUSIONS: Functional neural abnormalities can be observed during wakefulness in somnambulism, particularly after sleep deprivation and in the inferior temporal cortex. Sleep deprivation thus not only facilitates the occurrence of sleepwalking episodes, but also uncovers patterns of neural dysfunction that characterize sleepwalkers during wakefulness.

Integrated theory to unify status among schizophrenia and manic depressive illness.

Tryptophan hydroxylase 1 is primarily expressed in the gastrointestinal tract, and has been associated with both schizophrenia and depression. Although decreased serotonin activity has been reported in both depression and mania, it is important to investigate the interaction between serotonin and other neurotransmitter systems. There are competitive relationships between branched-chain amino acids, and tryptophan and tyrosine that relate to physical activity, and between L-3,4-dihydroxyphenylalanine (L-DOPA) and 5-hydroxytryptophan (5-HTP), both highly dependent on intracellular tetrahydrobiopterin concentrations. Here, I propose a chaos theory for schizophrenia, mania, and depression using the competitive interaction between tryptophan and tyrosine with regard to the blood-brain barrier and coenzyme tetrahydrobiopterin. Mania may be due to the initial conditions of physical hyperactivity and hypofunctional 5-HTP-producing cells inducing increased dopamine. Depression may be due to the initial conditions of physical hypoactivity and hypofunctional 5-HTP-producing cells inducing decreased serotonin. Psychomotor excitation may be due to the initial conditions of physical hyperactivity and hyperfunctional 5-HTP-producing cells inducing increased serotonin and substantially increased dopamine. The hallucinatory-paranoid state may be due to the initial conditions of physical hypoactivity and hyperfunctional 5-HTP-producing cells inducing increased serotonin and dopamine.

Effect of cataract surgery on cognition, mood, and visual hallucinations in older adults.

PURPOSE: To assess the impact of cataract surgery on cognition, mood, and visual hallucinations in a cohort of patients aged 75 years and older. SETTING: Secondary care ophthalmology unit in Northeast England. DESIGN: Prospective observational cohort study. METHODS: Participants aged 75 years or older with bilateral cataract and scheduled for cataract surgery were recruited consecutively. Participants were assessed preoperatively and followed for 1 year postoperatively. Cognition was assessed using the revised Addenbrooke's Cognitive Examination (ACE-R), mood was measured with the 15-item Geriatric Depression Scale, visual hallucinations were elicited using the North East Visual Hallucinations Inventory, and visual acuity was assessed using a logMAR chart. RESULTS: One hundred twelve participants were recruited at baseline; 91 (81%) completed 1 year of follow-up. Significant improvements in ACE-R scores were seen between baseline and 1 year postoperatively (95% confidence interval for improvement, 0.5-2.8; P = .005). Improved cognition did not correlate with improved visual acuity (r = -0.13, P = .22). No significant changes in mood were seen during the course of the study (P = .314, repeated-measures 1-way analysis of variance). Complete resolution of complex visual hallucinations occurred in 2 patients after surgery. CONCLUSIONS: Small improvements in cognition and reports of resolved complex visual hallucinations indicate that the benefits of cataract surgery might extend beyond visual improvement. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Locus coeruleus syndrome as a complication of tectal surgery.

We describe a case of a 48-year-old woman who underwent a resection of a tectal pilocytic astrocytoma complicated by a sequence of fluctuating consciousness, psychosis with complex hallucinations and lasting sleeping disturbances in which she vividly acts out her dreams. Based on the clinical and anatomical evidence of this case, we propose the term locus coeruleus syndrome to describe this association of iatrogenic symptoms. Along with those of the locus coeruleus, lesions of the dorsal raphe nucleus, ventral tegmentum, substantia nigra pars compacta, the superior colliculus and other peduncular lesions (such as peduncular hallucinosis) are involved in the regulation of sleep-wake/arousal, behaviour, sleeping disorders and rapid eye movement atonia. However, iatrogenic lesion of the locus coeruleus could explain the complications on all levels in our patient.

Visual hallucinations of autobiographic memory and asomatognosia: a case of epilepsy due to brain cysticercosis.

The current study describes the case of a woman with symptomatic epilepsy due to brain cysticercosis acquired during childhood. During her adolescence, she developed seizures characterized by metamorphopsia, hallucinations of autobiographic memory and, finally, asomatognosia. Magnetic brain imaging showed a calcified lesion in the right occipitotemporal cortex, and positron emission tomography imaging confirmed the presence of interictal hypometabolism in two regions: the right parietal cortex and the right lateral and posterior temporal cortex. We discuss the link between these brain areas and the symptoms described under the concepts of epileptogenic lesion, epileptogenic zone, functional deficit zone, and symptomatogenic zone.