Connectome-based predictive modeling predicts paranoid ideation in young men with paranoid personality disorder: a resting-state functional magnetic resonance imaging study.

Paranoid personality disorder (PPD), a mental disorder that affects interpersonal relationships and work, is frequently neglected during diagnosis and evaluation at the individual-level. This preliminary study aimed to investigate whether connectome-based predictive modeling (CPM) can predict paranoia scores of young men with PPD using whole-brain resting-state functional connectivity (rs-FC). College students with paranoid tendencies were screened using paranoia scores ≥60 derived from the Minnesota Multiphasic Personality Inventory; 18 participants were ultimately diagnosed with PPD according to the Diagnostic and Statistical Manual of Mental Disorders and subsequently underwent resting-state functional magnetic resonance imaging. Whole-brain rs-FC was constructed, and the ability of this rs-FC to predict paranoia scores was evaluated using CPM. The significance of the models was assessed using permutation tests. The model constructed based on the negative prediction network involving the limbic system-temporal lobe was observed to have significant predictive ability for paranoia scores, whereas the model constructed using the positive and combined prediction network had no significant predictive ability. In conclusion, using CPM, whole-brain rs-FC predicted the paranoia score of patients with PPD. The limbic system-temporal lobe FC pattern is expected to become an important neurological marker for evaluating paranoid ideation.

Methamphetamine (MA) Use Induces Specific Changes in LINE-1 Partial Methylation Patterns, Which Are Associated with MA-Induced Paranoia: a Multivariate and Neuronal Network Study.

The use of psychoactive substances, including methamphetamine (MA) may cause changes in DNA methylation. The aim of this study was to examine the effects of MA use on long interspersed element-1 (LINE-1) methylation patterns in association with MA-induced paranoia. This study recruited 123 normal controls and 974 MA users, 302 with and 672 without MA-induced paranoia. The Semi-Structured Assessment for Drug Dependence and Alcoholism was used to assess demographic and substance use variables. Patterns of LINE-1 methylation were assessed in peripheral blood mononuclear cells and a combined bisulfite restriction analysis (COBRA) was used to estimate overall LINE-1 methylation (mC) while COBRA classified LINE-alleles into four patterns based on the methylation status of two CpG dinucleotides on each strand from 5' to 3', namely two methylated (mCmC) and two unmethylated (uCuC) CpGs and two types of partially methylated loci (mCuC that is 5'm with 3'u and uCmC that is 5'u with 3'm CpGs). MA users showed higher % mCuC and % mCuC + uCmC levels than controls. Use of solvents and opioids, but not cannabis and alcohol dependence, significantly lowered % uCmC levels, while current smoking significantly increased % uCuC levels. MA-induced paranoia was strongly associated with changes in LINE-1 partial methylation patterns (lowered % uCmC), heavy MA use, lower age at onset of MA use, and alcohol dependence. Women who took contraceptives showed significantly lower LINE-1 % mC and % mCmC and higher % uCuC levels than women without contraceptive use and men. The results show that MA-induced changes in LINE-1 partial methylation patterns are associated with MA-induced paranoia and could explain in part the pathophysiology of this type of psychosis. It is argued that MA-induced neuro-oxidative pathways may have altered LINE-1 partial methylation patterns, which in turn may regulate neuro-oxidative and immune pathways, which may increase risk to develop MA-induced paranoia.

Capgras Syndrome and Other Delusional Misidentification Syndromes.

The delusional misidentification syndromes (DMS) are a group of disorders, characterized by patients mistaking the identity of people they know, although they recognize them physically. The term DMS is an umbrella term which may cover disorders whose definition extends to objects other than people, such as animals, places, or familiar material objects. The most common and best known DMS is Capgras syndrome. In this disorder, the misidentification leads to the delusional conviction that a close friend or relative has been replaced by an identical - or almost identical - "double," whose original has disappeared. This double is an imposter without name or identity. Most often considered as a persecutor, the double may be subjected to aggression, which may be very violent. Neuropsychological hypotheses based on cerebral dysfunctions are now commonly considered to be at the origin of the disorder. They have been elaborated from achievements in the neurosciences, particularly the facial recognition models. In return, knowledge about the normal cognitive processes involved in recognition and familiarity has benefited from the work that cognitive neuropsychiatry has invested in these disorders. The DMS are observed in various contexts of morbidity: primary psychiatric diagnosis, or secondary to various organic disorders, particularly in neurodegenerative disease; they are rarely met in isolated form. Most often, they develop in line with the associated pathology. In the absence of consensual clinical description, the epidemiology of DMS is uncertain; they may be more frequent than previously supposed. There is no specific treatment for these disorders; neuroleptics are generally used in association with treatment of the concomitant disorder. The frequent association of DMS with organic disorders which may be curable and the particularly dangerous profile of these patients are factors that underline the need for better screening.

Differences in Connection Strength between Mental Symptoms Might Be Explained by Differences in Variance: Reanalysis of Network Data Did Not Confirm Staging.

BACKGROUND: The network approach to psychopathology conceives mental disorders as sets of symptoms causally impacting on each other. The strengths of the connections between symptoms are key elements in the description of those symptom networks. Typically, the connections are analysed as linear associations (i.e., correlations or regression coefficients). However, there is insufficient awareness of the fact that differences in variance may account for differences in connection strength. Differences in variance frequently occur when subgroups are based on skewed data. An illustrative example is a study published in PLoS One (2013;8(3):e59559) that aimed to test the hypothesis that the development of psychopathology through "staging" was characterized by increasing connection strength between mental states. Three mental states (negative affect, positive affect, and paranoia) were studied in severity subgroups of a general population sample. The connection strength was found to increase with increasing severity in six of nine models. However, the method used (linear mixed modelling) is not suitable for skewed data. METHODS: We reanalysed the data using inverse Gaussian generalized linear mixed modelling, a method suited for positively skewed data (such as symptoms in the general population). RESULTS: The distribution of positive affect was normal, but the distributions of negative affect and paranoia were heavily skewed. The variance of the skewed variables increased with increasing severity. Reanalysis of the data did not confirm increasing connection strength, except for one of nine models. CONCLUSIONS: Reanalysis of the data did not provide convincing evidence in support of staging as characterized by increasing connection strength between mental states. Network researchers should be aware that differences in connection strength between symptoms may be caused by differences in variances, in which case they should not be interpreted as differences in impact of one symptom on another symptom.

Evidence that a psychopathology interactome has diagnostic value, predicting clinical needs: an experience sampling study.

BACKGROUND: For the purpose of diagnosis, psychopathology can be represented as categories of mental disorder, symptom dimensions or symptom networks. Also, psychopathology can be assessed at different levels of temporal resolution (monthly episodes, daily fluctuating symptoms, momentary fluctuating mental states). We tested the diagnostic value, in terms of prediction of treatment needs, of the combination of symptom networks and momentary assessment level. METHOD: Fifty-seven patients with a psychotic disorder participated in an ESM study, capturing psychotic experiences, emotions and circumstances at 10 semi-random moments in the flow of daily life over a period of 6 days. Symptoms were assessed by interview with the Positive and Negative Syndrome Scale (PANSS); treatment needs were assessed using the Camberwell Assessment of Need (CAN). RESULTS: Psychotic symptoms assessed with the PANSS (Clinical Psychotic Symptoms) were strongly associated with psychotic experiences assessed with ESM (Momentary Psychotic Experiences). However, the degree to which Momentary Psychotic Experiences manifested as Clinical Psychotic Symptoms was determined by level of momentary negative affect (higher levels increasing probability of Momentary Psychotic Experiences manifesting as Clinical Psychotic Symptoms), momentary positive affect (higher levels decreasing probability of Clinical Psychotic Symptoms), greater persistence of Momentary Psychotic Experiences (persistence predicting increased probability of Clinical Psychotic Symptoms) and momentary environmental stress associated with events and activities (higher levels increasing probability of Clinical Psychotic Symptoms). Similarly, the degree to which momentary visual or auditory hallucinations manifested as Clinical Psychotic Symptoms was strongly contingent on the level of accompanying momentary paranoid delusional ideation. Momentary Psychotic Experiences were associated with CAN unmet treatment needs, over and above PANSS measures of psychopathology, similarly moderated by momentary interactions with emotions and context. CONCLUSION: The results suggest that psychopathology, represented as an interactome at the momentary level of temporal resolution, is informative in diagnosing clinical needs, over and above traditional symptom measures.

Attenuated prefrontal activation during decision-making under uncertainty in schizophrenia: a multi-center fMRI study.

Decisions are called decisions under uncertainty when either prior information is incomplete or the outcomes of the decision are unclear. Alterations in these processes related to decisions under uncertainty have been linked to delusions. In patients with schizophrenia, the underlying neural networks have only rarely been studied. We aimed to disentangle the neural correlates of decision-making and relate them to neuropsychological and psychopathological parameters in a large sample of patients with schizophrenia and healthy subjects. Fifty-seven patients and fifty-seven healthy volunteers from six centers had to either indicate via button-press from which of two bottles red or blue balls were drawn (decision-making under uncertainty condition), or indicate whether eight red balls had been presented (baseline condition) while BOLD signal was measured with fMRI. Patients based their decisions on less conclusive evidence and had decreased activations in the underlying neural network, comprising of medial and lateral frontal as well as parietal areas, as compared to healthy subjects. While current psychopathology was not correlated with brain activation, positive symptoms led to longer decision latencies in patients. These results suggest that decision-making under uncertainty in schizophrenia is affected by a complex interplay of aberrant neural activation. Furthermore, reduced neuropsychological functioning in patients was related to impaired decision-making and task performance was modulated by distinct positive symptoms.

Frontotemporal atrophy associated with paranoid delusions in women with Alzheimer's disease.

BACKGROUND: Paranoid delusions are a common and difficult-to-manage feature of Alzheimer's disease (AD). We investigated the neuroanatomical correlates of paranoid delusions in a cohort of AD patients, using magnetic resonance imaging (MRI) to measure regional volume and regional cortical thickness. METHODS: 113 participants with probable AD were assessed for severity of disease, cognitive and functional impairment. Presence and type of delusions were assessed using the Neuropsychiatric Inventory (NPI). Structural MRI images were acquired on a 1.5 T scanner, and were analyzed using an automated analysis pipeline. RESULTS: Paranoid delusions were experienced by 23 (20.4%) of the participants. Female participants with paranoid delusions showed reduced cortical thickness in left medial orbitofrontal and left superior temporal regions, independently of cognitive decline. Male participants with delusions did not show any significant differences compared to males without delusions. An exploratory whole brain analysis of non-hypothesized regions showed reduced cortical thickness in the left insula for female participants only. CONCLUSION: Frontotemporal atrophy is associated with paranoid delusions in females with AD. Evidence of sex differences in the neuroanatomical correlates of delusions as well as differences in regional involvement in different types of delusions may be informative in guiding management and treatment of delusions in AD.

The spectrum of sociopathy in dementia.

Although well-known from head trauma and acute strokes, sociopathic behavior from dementia is less known and understood. This study reviewed 33 dementia patients who had been in trouble with the law. They were divided into two groups: 22 who committed impulsive sociopathic acts and 11 who committed non-impulsive acts. The impulsive patients demonstrated nonviolent acts, such as disinhibited sexual behavior or pathological stealing, and had disproportionate frontal-caudate atrophy on neuroimaging. The majority of non-impulsive patients demonstrated agitation-paranoia, sometimes with reactive aggression, delusional beliefs, or aphasic paranoia, and had advanced memory and other cognitive impairment. The impulsive patients tended to have frontally predominant illnesses such as frontotemporal dementia or Huntington's disease, whereas the non-impulsive group tended to have Alzheimer's disease or prominent aphasia. Sociopathy has different causes in dementia. Two common mechanisms are disinhibition, with frontally predominant disease, and agitation-paranoia, with greater cognitive impairment. These forms of sociopathy differ significantly from the antisocial/psychopathic personality.

A propósito de la locura del hidalgo Alonso Quijano en el marco de la medicina española tardorrenacentista / With regard t the madness of nobleman Alonso Quijano within the framework of the Spanish late Renaissance medicine

Introducción: El Quijote es una de las obras literarias más analizadas desde la perspectiva psicopatológica., bien con el objetivo de obtener un diagnóstico psiquiátrico de su principal personaje, Alonso Quijano, o de recabar datos para conocer más profundamente el concepto de locura en la sociedad renacentista tardía española. En el presente trabajo se pretende efectuar un enfoque sintético y revisionista a lo mucho que se ha escrito sobre el posible trastorno mental de Alonso Quijano, siempre en el contexto de la época en que fue escrita la novela, así como analizar la evolución de su conceptualización diagnóstica a través del tiempo: monomanía, paranoia, trastorno delirante, mitomanía histérica, trastorno bipolar, demencia presenil, etc. También se analizan las posibles influencias científicas en que se pudo inspirar Cervantes en este campo, fundamentalmente la obra de Juan Huarte de San Juan (Examen de ingenios para las ciencias) y de Ersmo de Rottermdam (Elogio de la Locura), así como los remedios terapéuticos a los que recurre el autor para el manejo de los síntomas psiquiátricos de su alienado personaje

Introduction: Don Quixote has been a novel frequently approached from the psychopathological perspective to obtain a psychiatric diagnosis of its main character, Alonso Quijano, or obtain data about the madness concept in the Spanish late Renaissance society. In the present work, we intend to carry out a synthetic and revisionist approach to much that it has been written on the possible mental disorder of Alonso Quijano, always in the time context in which the novel was written, as well as to analyzed the evolution of its diagnostic conceptualization through the time: monomania, paranoia, delusional disorder, hysterical mitomania, bipolar disorder, presenile dementia, etc. Also, we have review the possible scientific influences which might have inspired Cervantes in this field, mainly the work of Juan Huarte de San Juan (The examination of men´s wits) and the one of Erasmus of rotterman (The praise of folly), as well as the therapeutic remedies to which the author resort for the handling of the psychiatric symptoms of his aliened personage

Hallucinations, REM sleep, and Parkinson's disease: a medical hypothesis.

BACKGROUND: Patients with PD can have disabling visual hallucinations associated with dopaminergic therapy. Sleep disorders, including vivid dreams and REM sleep with motor behaviors (RBD), are frequent in these patients. METHODS: The association of hallucinations and REM sleep both at night and during the day was examined in 10 consecutive nondemented patients with long-standing levodopa-responsive PD and hallucinations. Seven patients presented with paranoia and paranoid delusions. Overnight sleep recordings and standard multiple daytime sleep latency test were performed. The results were compared to those of 10 similar patients with PD not experiencing hallucinations. RESULTS: RBD was detected in all 10 patients with hallucinations and in six without. Although nighttime sleep conditions were similar in both groups, hallucinators tended to be sleepier during the day. Delusions following nighttime REM period and daytime REM onsets were observed in three and eight of the hallucinators, and zero and two of the others. Daytime hallucinations, coincident with REM sleep intrusions during periods of wakefulness, were reported only by hallucinators. Postmortem examination of the brain of one patient showed numerous Lewy bodies in neurons of the subcoeruleus nucleus, a region that is involved in REM sleep control. CONCLUSION: The visual hallucinations that coincide with daytime episodes of REM sleep in patients who also experience post-REM delusions at night may be dream imagery. Psychosis in patients with PD may therefore reflect a narcolepsy-like REM sleep disorder.

Late-onset paranoid psychosis as a distinct clinicopathologic entity: magnetic resonance imaging data in elderly patients with paranoid psychosis of late onset and schizophrenia of early onset.

OBJECTIVE: The aim of this study is to equalize the influence of age-related changes and to test the hypothesis that specific structural brain changes are mediating the development of unique clinical features in late-onset paranoid psychosis (LOPP). BACKGROUND: Findings of unique white matter lesions have been recently described in patients with LOPP. These findings have not been consistent, however, when age-matched normal subjects have been used as a control group. METHOD: Magnetic resonance imaging data were compared in 13 patients with LOPP, mean age 66.33, and 35 elderly patients with early-onset paranoid schizophrenia (PSCH), mean age 63.89. Patients in the LOPP group differed from the PSCH group by the mild degree or absence of negative symptoms, the absence of formal thought disorders, and by prevalence of female patients. RESULTS: Analysis of the magnetic resonance imaging data revealed statistically significant differences between the LOPP and PSCH groups. White matter hyperintensity was almost threefold more frequent in LOPP than in PSCH groups, 69.2% versus 22.9% respectively. Ventricular enlargement and cortical atrophy were more frequent in the PSCH group, reaching, for moderate to severe abnormalities, 28.6% for ventricular enlargement and 22.9% for cortical atrophy; moderate to severe abnormalities were absent in all 13 patients of the LOPP group. CONCLUSIONS: These data point to the possibility that late-onset paranoid psychosis is a distinct clinicopathological entity, with white matter hyperintensity mediating the development of LOPP in a significant percentage of the cases. The vascular origin of white matter lesions in LOPP is suggested.

Neuropathological and neuroradiological correlates of paranoid symptoms in organic mental disease.

This paper reviews paranoid symptoms in older patients with organic mental disease. We have taken a dual approach to this topic, examining patients with dementia in whom paranoid symptoms are present and also assessing the presence of organic brain changes in patients diagnosed as having late-onset schizophrenia, paraphrenia or delusional disorder. (For the sake of continuity and not wishing to pre-empt any discussion of the nosological categorisation of late-onset psychoses, we refer to late-onset persecutory state as paraphrenia.) Firstly, there is a description of the various paranoid symptoms which have been described in patients with dementia. Secondly, brain imaging studies are discussed which have highlighted changes in patients with paraphrenia and particular associations between psychotic phenomenology and brain changes in patients with dementia. Thirdly, neuropathological and neurochemical changes in the brains of patients with dementia in whom paranoid symptoms have been present are presented. We intersperse all three sections with data from work carried out by the authors at the Institute of Psychiatry in London from 1986 and 1992. For other reviews, see Allen and Burns (1995), Burns and Förstl (1996), Eisiri (1996) and Howard (1996).

Delusional disorders are a naturally occurring 'experimental psychosis'.

A delusion can only be 'explained' if it can be correlated with a demonstrable brain event, and this is only beginning to be possible. The misidentification syndromes are leading the way in demonstrating a close relationship between quite specific brain abnormalities and highly characteristic delusional symptoms. Although delusional disorder (DSM-IV 297.10) and its treatment are well described, virtually no investigations have been carried out on the neuropathological substrate. This article suggests that delusional disorder is a naturally occurring 'model psychosis' which would reward experimental study.

Lipoid proteinosis presenting with neuropsychiatric manifestations.

Two patients with lipoid proteinosis are reported in whom paranoid symptoms were the presenting feature. Both had a long standing impairment of memory and bilateral medial temporal lobe calcification demonstrated by CT scan. Possible associations between the anatomical site of these lesions and the neuropsychiatric manifestations are discussed.