Basal-Forebrain Cholinergic Nuclei Alterations are Associated With Medication and Cognitive Deficits Across the Schizophrenia Spectrum

© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.[Background and Hypothesis] The cholinergic system is altered in schizophrenia. Particularly, patients’ volumes of basal-forebrain cholinergic nuclei (BFCN) are lower and correlated with attentional deficits. It is unclear, however, if and how BFCN changes and their link to cognitive symptoms extend across the schizophrenia spectrum, including individuals with at-risk mental state for psychosis (ARMS) or during first psychotic episode (FEP).[Study Design] To address this question, we assessed voxel-based morphometry (VBM) of structural magnetic resonance imaging data of anterior and posterior BFCN subclusters as well as symptom ratings, including cognitive, positive, and negative symptoms, in a large multi-site dataset (n = 4) comprising 68 ARMS subjects, 98 FEP patients (27 unmedicated and 71 medicated), 140 patients with established schizophrenia (SCZ; medicated), and 169 healthy controls.[Results] In SCZ, we found lower VBM measures for the anterior BFCN, which were associated with the anticholinergic burden of medication and correlated with patients’ cognitive deficits. In contrast, we found larger VBM measures for the posterior BFCN in FEP, which were driven by unmedicated patients and correlated at-trend with cognitive deficits. We found no BFCN changes in ARMS. Altered VBM measures were not correlated with positive or negative symptoms.[Conclusions] Results demonstrate complex (posterior vs. anterior BFCN) and non-linear (larger vs. lower VBM) differences in BFCN across the schizophrenia spectrum, which are specifically associated both with medication, including its anticholinergic burden, and cognitive symptoms. Data suggest an altered trajectory of BFCN integrity in schizophrenia, influenced by medication and relevant for cognitive symptoms.M.K. acknowledges support from the National Bank Fellowship (McGill University) and the Swiss National Foundation (P2SKP3_178175). F.B. was supported by the Else Kröner Memorial Stipendium and the Hans und Klementia Langmatz Foundation. C.S. was supported by the German Federal Ministry of Education and Research (BMBF; 01ER0803) and the German Research Council (DFG; SO1336/7).Peer reviewe

Individualized prediction of psychosis in subjects with an at-risk mental state

Early intervention strategies in psychosis would significantly benefit from the identification of reliable prognostic biomarkers. Pattern classification methods have shown the feasibility of an early diagnosis of psychosis onset both in clinical and familial high-risk populations. Here we were interested in replicating our previous classification findings using an independent cohort at clinical high risk for psychosis, drawn from the prospective FePsy (Fruherkennung von Psychosen) study. The same neuroanatomical-based pattern classification pipeline, consisting of a linear Support Vector Machine (SVM) and a Recursive Feature Selection (RFE) achieved 74% accuracy in predicting later onset of psychosis. The discriminative neuroanatomical pattern underlying this finding consisted of many brain areas across all four lobes and the cerebellum. These results provide proof-of-concept that the early diagnosis of psychosis is feasible using neuroanatomical-based pattern recognition

Hippocampus abnormalities in at risk mental states for psychosis? A cross-sectional high resolution region of interest magnetic resonance imaging study

Background: Hippocampal volume (HV) reduction is well documented in schizophrenia. However, it is still unclear whether this change is a pre-existing vulnerability factor, a sign of disease progression, a consequence of environmental factors, such as drug use, antipsychotic medication, or malnutrition. The timing of HV changes is not well established, but a lack of macrostructural hippocampal brain abnormalities before disease onset would rather support a neuroprogressive illness model. Aim: To investigate the timing of HV changes in emerging psychosis. Methods: A cross-sectional MRI study of manually traced HVs in 37 individuals with an At Risk Mental State (ARMS) for psychosis, 23 individuals with First-Episode Psychosis (FEP), and 22 Healthy Controls (HC) was performed. We compared left and right HVs corrected for whole brain volume across groups using analysis of covariance (ANCOVA) with gender as a covariate. Sixteen of 37 ARMS individuals developed a psychotic disorder during follow up (ARMS-T). The mean duration of follow up in ARMS was 25.1 months. Results: The overall ANCOVA model comparing left HVs across FEP, ARMS and HC indicated a significant general group effect (p < .05) with largest volumes in ARMS and smallest in FEP. ARMS-T subjects had significantly larger left HVs compared to FE but no HV differences compared to HC (p < 0.05). Over all groups, we found an asymmetry between the left and right mean HVs and a strong effect of sex. Discussion: The present study suggests that macrostructural hippocampal abnormalities probably occur in the context of the first psychotic breakdown

Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

Rationale 3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects.; We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI).; All active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects.; MDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used

Dysfunctional insular connectivity during reward prediction in patients with first-episode psychosis

Background: Increasing evidence indicates that psychosis is associated with abnormal reward processing. Imaging studies in patients with first-episode psychosis (FEP) have revealed reduced activity in diverse brain regions, including the ventral striatum, insula and anterior cingulate cortex (ACC), during reward prediction. However, whether these reductions in local brain activity are due to altered connectivity has rarely been explored. Methods: We applied dynamic causal modelling and Bayesian model selection to fMRI data during the Salience Attribution Task to investigate whether patients with FEP showed abnormal modulation of connectivity between the ventral striatum, insula and ACC induced by rewarding cues and whether these changes were related to positive psychotic symptoms and atypical antipsychotic medication. Results: The model including reward-induced modulation of insula-ACC connectivity was the best fitting model in each group. Compared with healthy controls (n = 19), patients with FEP (n = 29) revealed reduced right insula-ACC connectivity. After subdividing patients according to current antipsychotic medication, we found that the reduced insula-ACC connectivity relative to healthy controls was observed only in untreated patients (n = 17), not in patients treated with antipsychotics (n = 12), and that it correlated negatively with unusual thought content in untreated patients with FEP. Limitations: The modest sample size of untreated patients with FEP was a limitation of our study. Conclusion: This study indicates that insula-ACC connectivity during reward prediction is reduced in untreated patients with FEP and related to the formation of positive psychotic symptoms. Our study further suggests that atypical antipsychotics may reverse connectivity between the insula and the ACC during reward prediction

Pituitary gland volume in at-risk mental state for psychosis: a longitudinal MRI analysis

Introduction: Pituitary enlargement has been reported in individuals with schizophrenic psychosis or an at-risk mental state for psychosis (ARMS). In a previous study, our group could show pituitary volume increase in first episode and ARMS patients with later transition to psychosis (ARMS-T). However, there are no longitudinal studies on this issue so far. We therefore examined longitudinally whether transition to psychosis would be accompanied by a further increase of pituitary volume in antipsychotic-naive ARMS patients. METHODS: Magnetic resonance imaging (MRI) data were acquired from 23 antipsychotic-naive individuals with an ARMS. Ten subjects developed psychosis (ARMS-T) and 13 did not (ARMS-NT). ARMS-T were re-scanned after the onset of psychosis, and ARMS-NT were re-scanned at the end of the study period. RESULTS: There was no significant difference of the pituitary volume between ARMS-T and ARMS-NT in our sample, and there were no significant pituitary volume changes over time. Discussion Longitudinally, we could not detect any further volumetric changes in the pituitary volume with transition to psychosis. CONCLUSIONS: This, together with the result of our previous study, could indicate that the perceived level of stress in ARMS patients is constantly high from very early onward

The impact of diacetylmorphine on hypothalamic-pituitary-adrenal axis activity and heroin craving in heroin dependence

Background/Aim: Heroin dependence is a chronic relapsing disorder characterized by the compulsion to seek and use heroin. Stress and craving are seen as key factors for heroin use. Moreover, altered hypothalamic-pituitary-adrenal (HPA) axis function has been frequently reported. However, the acute effects of diacetylmorphine (DAM) on HPA axis activity and craving have not been investigated in a controlled study. The present randomized controlled study examined whether DAM administration differs from placebo (saline) administration with regard to HPA axis response and heroin craving. Methods: In a crossover experiment, 28 DAM-maintained heroin-dependent patients were first injected with DAM and then saline, or the converse. Plasma adrenocorticotropic hormone (ACTH) and cortisol in saliva and serum were measured at baseline and 20 and 60 min after both injections. Heroin craving was measured at baseline and 60 min after both injections, by means of the Heroin Craving Questionnaire. Results: Compared to saline, DAM administration induced a significant decrease in plasma ACTH (p &lt; 0.01), serum cortisol (p &lt; 0.0001) and saliva cortisol (p &lt; 0.01), as well as in craving (p &lt; 0.0001), over time. Conclusion: Since acute DAM administration suppresses the stress response, DAM-assisted treatment may be an effective alternative to methadone maintenance in stress-sensitive heroin-dependent patients

Evidence from comprehensive independent validation studies for smooth pursuit dysfunction as a sensorimotor biomarker for psychosis

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis

Association between age of cannabis initiation and gray matter covariance networks in recent onset psychosis

Cannabis use during adolescence is associated with an increased risk of developing psychosis. According to a current hypothesis, this results from detrimental effects of early cannabis use on brain maturation during this vulnerable period. However, studies investigating the interaction between early cannabis use and brain structural alterations hitherto reported inconclusive findings. We investigated effects of age of cannabis initiation on psychosis using data from the multicentric Personalized Prognostic Tools for Early Psychosis Management (PRONIA) and the Cannabis Induced Psychosis (CIP) studies, yielding a total sample of 102 clinically-relevant cannabis users with recent onset psychosis. GM covariance underlies shared maturational processes. Therefore, we performed source-based morphometry analysis with spatial constraints on structural brain networks showing significant alterations in schizophrenia in a previous multisite study, thus testing associations of these networks with the age of cannabis initiation and with confounding factors. Earlier cannabis initiation was associated with more severe positive symptoms in our cohort. Greater gray matter volume (GMV) in the previously identified cerebellar schizophrenia-related network had a significant association with early cannabis use, independent of several possibly confounding factors. Moreover, GMV in the cerebellar network was associated with lower volume in another network previously associated with schizophrenia, comprising the insula, superior temporal, and inferior frontal gyrus. These findings are in line with previous investigations in healthy cannabis users, and suggest that early initiation of cannabis perturbs the developmental trajectory of certain structural brain networks in a manner imparting risk for psychosis later in life

The heterogeneity of attenuated and brief limited psychotic symptoms: association of contents with age, sex, country, religion, comorbidities, and functioning

INTRODUCTION The Attenuated Psychosis Symptoms (APS) syndrome mostly represents the ultra-high-risk state of psychosis but, as does the Brief Intermittent Psychotic Symptoms (BIPS) syndrome, shows a large variance in conversion rates. This may be due to the heterogeneity of APS/BIPS that may be related to the effects of culture, sex, age, and other psychiatric morbidities. Thus, we investigated the different thematic contents of APS and their association with sex, age, country, religion, comorbidity, and functioning to gain a better understanding of the psychosis-risk syndrome. METHOD A sample of 232 clinical high-risk subjects according to the ultra-high risk and basic symptom criteria was recruited as part of a European study conducted in Germany, Italy, Switzerland, and Finland. Case vignettes, originally used for supervision of inclusion criteria, were investigated for APS/BIPS contents, which were compared for sex, age, country, religion, functioning, and comorbidities using chi-squared tests and regression analyses. RESULT We extracted 109 different contents, mainly of APS (96.8%): 63 delusional, 29 hallucinatory, and 17 speech-disorganized contents. Only 20 contents (18.3%) were present in at least 5% of the sample, with paranoid and referential ideas being the most frequent. Thirty-one (28.5%) contents, in particular, bizarre ideas and perceptual abnormalities, demonstrated an association with age, country, comorbidity, or functioning, with regression models of country and obsessive-compulsive disorders explaining most of the variance: 55.8 and 38.3%, respectively. Contents did not differ between religious groups. CONCLUSION Psychosis-risk patients report a wide range of different contents of APS/BIPS, underlining the psychopathological heterogeneity of this group but also revealing a potential core set of contents. Compared to earlier reports on North-American samples, our maximum prevalence rates of contents were considerably lower; this likely being related to a stricter rating of APS/BIPS and cultural influences, in particular, higher schizotypy reported in North-America. The various associations of some APS/BIPS contents with country, age, comorbidities, and functioning might moderate their clinical severity and, consequently, the related risk for psychosis and/or persistent functional disability