Persistent Auditory Hallucinations Research Articles

Correlation Between Cortical Thickness Abnormalities of the Olfactory Sulcus and Olfactory Identification Disorder and Persistent Auditory Verbal Hallucinations in Chinese Patients With Chronic Schizophrenia.

Persistent auditory verbal hallucinations (pAVHs) and olfactory identification impairment are common in schizophrenia (SCZ), but the neuroimaging mechanisms underlying both pAVHs and olfactory identification impairment are unclear. This study aimed to investigate whether pAVHs and olfactory identification impairment in SCZ patients are associated with changes in cortical thickness. In this study, cortical thickness was investigated in 78 SCZ patients with pAVHs (pAVH group), 58 SCZ patients without AVHs (non-AVH group), and 83 healthy controls (HC group) using 3T magnetic resonance imaging. The severity of pAVHs was assessed by the Auditory Hallucination Rating Scale. Olfactory identification deficits were assessed using the Odor Stick Identification Test for Japanese (OSIT-J). In addition, the relationship between the severity of pAVHs and olfactory identification disorder and cortical thickness abnormalities was determined. Significant reductions in cortical thickness were observed in the right medial orbital sulcus (olfactory sulcus) and right orbital sulcus (H-shaped sulcus) in the pAVH group compared to both the non-AVH and HC groups (P < .003, Bonferroni correction). Furthermore, the severity of pAVHs was found to be negatively correlated with the reduction in cortical thickness in the olfactory sulcus and H-shaped sulcus. Additionally, a decrease in cortical thickness in the olfactory sulcus showed a positive correlation with the OSIT-J scores (P < .05, false discovery rate correction). Cortical thickness abnormalities in the olfactory sulcus may be a common neuroimaging mechanism for pAVHs and olfactory identification deficits in SCZ patients.

Study protocol for identifying resting brain functional connectivity markers of response to continuous Theta Burst Stimulation and cathodal transcranial Direct Current Stimulation in patients with schizophrenia with persistent auditory hallucinations

Background Schizophrenia is one of the most burdensome psychiatric disorders. Novel neuromodulatory techniques including cathodal transcranial direct current stimulation (c-tDCS) and continuous theta burst stimulation (cTBS) using repetitive transcranial magnetic stimulation (rTMS) are increasingly being used in alleviating the auditory verbal hallucinations that are persisting despite adequate antipsychotic treatment. Brain connectivity modulation by stimulating the left temporoparietal junction is thought to mediate these effects. The differential neurobiological mechanisms and efficacy of these two neuromodulation techniques are not known. We are unaware of any systematic studies that can guide clinicians in choosing between the two techniques. This protocol describes a parallel-arm, double-blind, randomized cross-over study to identify resting brain functional connectivity markers of response to cTBS and c-tDCS persistent auditory hallucinations to improve the efficacy of interventions. Methods Two hundred and ten consenting patients with schizophrenia with persistent auditory hallucinations will be randomly assigned to receive 15 days (30 sessions) of c-tDCS+sham-TBS or sham-tDCS+cTBS over the left temporoparietal region at three study centres. After a gap of 2-4 weeks, non-responders to the intervention will cross-over to the other arm. Clinical assessments, neurocognitive assessments, and multimodal investigations (magnetic resonance imaging, electroencephalography, heart rate variability, investigative transcranial magnetic stimulation-transcranial direct current stimulation, gene polymorphisms) will be conducted at baseline and repeated after the end of both phases of the trial. A differential pre-treatment resting brain functional connectivity signal will identify responders to cTBS or c-tDCS. Registration Clinical Trial Registry of India (CTRI/2021/05/033783) registered on 25/05/2021.

DRD4 VNTR 4/4 homozygosity as a genetic biomarker for treatment selection in patients with schizophrenia

ObjectiveThere seems to be an association between the DRD4 48-bp VNTR polymorphisms and antipsychotic treatment response, but there is a rare reference to confirm this finding. Hence, the present study tried to investigate the association between DRD4 48-bp VNTR polymorphisms and the treatment response of antipsychotics in patients with schizophrenia in Taiwan, using a propensity score matching (PSM) method. MethodsA total of 882 participants were enrolled in this study and completed informed consent, research questionnaires, including demographic information and the revised Chinese version Beliefs about Voices Questionnaire, and blood sampling. For descreasing of the selection bias and confounding variables, the PSM nearest neighbor matching method was used to select 765 paitents with schizophrenia (ratio of 1:8 between 85 persistent auditory hallucination and 680 controls) with matched and controlled the age and gender. ResultsSchizophrenia patients with DRD4 4 R homozygosity had a lower rate of good antipsychotic treatment response than the other DRD4 genotype carriers (DRD4 non-4/4). Among those 4 R homozygosity carriers, 60 cases of 503 (11.9%) retain persistent auditory hallucinations. Furthermore, this subgroup of patients is accounted for up to 70.6% of cases with poor neuroleptic treatment response. ConclusionsA poor treatment outcome for patients with the 4 R homozygosity had presented,that comparing with those DRD non-4/4 genotype carriers. DRD4 VNTR 4 R homozygosity could be a genetic biomarker to predict poor antipsychotic treatment response in schizophrenia. Patients with DRD 4/4 probably receive novel antipsychotic medications preferentially or in combination with alternative therapy, such as psychotherapy or milieu therapy.

40-Hz auditory steady-state response deficits are correlated with the severity of persistent auditory verbal hallucination in patients with schizophrenia

BackgroundAbnormal 40 Hz auditory steady-state response (ASSR) has been observed in some psychiatric disorders. Nevertheless, the role of 40 Hz ASSR in persistent auditory verbal hallucinations (pAVHs) schizophrenia (SCZ) is still unknown. This study aims to investigate whether the 40 Hz ASSR impairment is related to pAVHs and can detect pAVHs severity. MethodsWe analyzed high-density electroencephalography data that from 43 pAVHs patients (pAVH group), 20 moderate auditory verbal hallucinations patients (mid-AVH group), and 24 without auditory verbal hallucinations patients (non-AVH group). Event-related spectral perturbation and inter-trial phase coherence (ITPC) were calculated to quantify dynamic changes of the 40 Hz ASSR power and ITPC, respectively. ResultsFrontal-central, the 40 Hz ASSR power, and ITPC were significantly lower in the pAVH group than in the non-AVH group; There was no significant difference between the pAVH and mid-AVH group. The 40 Hz ASSR was significantly negatively correlated with the severity of pAVHs. The 40 Hz ASSR power, and ITPC could be used as a combinational marker to detect SCZ patients with and without pAVHs. ConclusionOur findings have shed light on the pathological mechanism of pAVHs in SCZ patients. These results can provide potential avenues for therapeutic intervention of pAVHs.

Volume alterations of the hippocampus and amygdala in patients with schizophrenia and persistent auditory hallucinations.

Auditory hallucinations (AH) are one of the most prevalent symptoms of schizophrenia. They might cause several brain alterations, especially changes in the volumes of hippocampus and amygdala, regions related to the relay and processing of auditory cues and emotional memories. We have recruited 41 patients with schizophrenia and persistent AH, 35 patients without AH, and 55 healthy controls. Using their MRIs, we have performed semiautomatic segmentations of the hippocampus and amygdala using Freesurfer. We have also performed bilateral correlations between the total PSYRATS score and the volumes of affected subregions and nuclei. In the hippocampus, we found bilateral increases in the volume of its hippocampal fissure and decreases in the right fimbria in patients with and without AH. The volume of the right hippocampal tail and left head of the granule cell layer from the dentate gyrus were decreased in patients with AH. In the amygdala, we found its left total volume was shrunk, and there was a decrease of its left accessory basal nucleus in patients with AH. We have detected volume alterations of different limbic structures likely due to the presence of AH. The volumes of the right hippocampal tail and left head of the granule cell layer from the dentate gyrus, and total volume of the amygdala and its accessory basal nucleus, were only affected in patients with AH. Bilateral volume alterations in the hippocampal fissure and right fimbria seem inherent of schizophrenia and due to traits not contemplated in our research.

Unsupervised Machine Learning Driven Analysis of Verbatims of Treatment-Resistant Schizophrenia Patients Having Followed Avatar Therapy.

(1) Background: The therapeutic mechanisms underlying psychotherapeutic interventions for individuals with treatment-resistant schizophrenia are mostly unknown. One of these treatment techniques is avatar therapy (AT), in which the patient engages in immersive sessions while interacting with an avatar representing their primary persistent auditory verbal hallucination. The aim of this study was to conduct an unsupervised machine-learning analysis of verbatims of treatment-resistant schizophrenia patients that have followed AT. The second aim of the study was to compare the data clusters obtained from the unsupervised machine-learning analysis with previously conducted qualitative analysis. (2) Methods: A k-means algorithm was performed over the immersive-session verbatims of 18 patients suffering from treatment-resistant schizophrenia who followed AT to cluster interactions of the avatar and the patient. Data were pre-processed using vectorization and data reduction. (3): Results: Three clusters of interactions were identified for the avatar's interactions whereas four clusters were identified for the patient's interactions. (4) Conclusion: This study was the first attempt to conduct unsupervised machine learning on AT and provided a quantitative insight into the inner interactions that take place during immersive sessions. The use of unsupervised machine learning could yield a better understanding of the type of interactions that take place in AT and their clinical implications.

Functional network interactions in patients with schizophrenia with persistent auditory verbal hallucinations: A multimodal MRI fusion approach using three-way pICA

Over the last decade, there have been an increasing number of functional magnetic resonance imaging (fMRI) studies examining brain activity in schizophrenia (SZ) patients with persistent auditory verbal hallucinations (AVH) using either task-based or resting-state fMRI (rs-fMRI) paradigms. Such data have been conventionally collected and analyzed as distinct modalities, disregarding putative crossmodal interactions. Recently, it has become possible to incorporate two or more modalities in one comprehensive analysis to uncover hidden patterns of neural dysfunction not sufficiently captured by separate analysis. A novel multivariate fusion approach to multimodal data analysis, i.e., parallel independent component analysis (pICA), has been previously shown to be a powerful tool in this regard. We utilized three-way pICA to study covarying components among fractional amplitude of low-frequency fluctuations (fALFF) for rs-MRI and task-based activation computed from an alertness and a working memory (WM) paradigm of 15 SZ patients with AVH, 16 non-hallucinating SZ patients (nAVH), and 19 healthy controls (HC). The strongest connected triplet (false discovery rate (FDR)-corrected pairwise correlations) comprised a frontostriatal/temporal network (fALFF), a temporal/sensorimotor network (alertness task), and a frontoparietal network (WM task). Frontoparietal and frontostriatal/temporal network strength significantly differed between AVH patients and HC. Phenomenological features such as omnipotence and malevolence of AVH were associated with temporal/sensorimotor and frontoparietal network strength. The transmodal data confirm a complex interplay of neural systems subserving attentional processes and cognitive control interacting with speech and language processing networks. In addition, the data emphasize the importance of sensorimotor regions modulating specific symptom dimensions of AVH.

Improving EEG Electrode Sensitivity with Graphene Nano Powder and Neural Network for Schizophrenia Diagnosis

Hallucinations and delusions are symptoms of schizophrenia. Due to persistent auditory and visual hallucinations, a person with schizophrenia cannot process reality clearly. Abnormal brain activity results from delusion and hallucination. During the capture of EEG signals, aberrant behavior is detected. The EEG electrodes do not well detect the brain's current distribution. Schizophrenia causes the EEG signal to be warped and less sensitive, which results in incorrect interpretation of brain activity. In this paper, an EEG electrode constructed of graphene nanopowder is suggested that is sensitive to the brain's weak electrical activity. The cold spray approach created graphene EEG electrodes, improving the material bonding and chemical characteristics. By obtaining EEG readings from schizophrenic patients, the sensitivity of the graphene electrode was assessed. The EEG signal was collected from the subject when taking part in cognitive tests like question sessions and numerical problems. Several neural networks (NN) algorithms can be used to identify hallucination and delusion aspects in EEG recordings. Further details regarding the hallucination and delusion aspects in the EEG signal were provided by the NN, showing a Graphene electrode. As compared to other NN models, the comparative study of several NN models revealed that the BFGS quasi-Newtonian backpropagation algorithm accurately recognized hallucination and delusion features.

Dyadic Interactions of Treatment-Resistant Schizophrenia Patients Having Followed Virtual Reality Therapy: A Content Analysis

(1) Background: Very little is known about the inner therapeutic processes of psychotherapy interventions for patients suffering from treatment-resistant schizophrenia. Avatar therapy (AT) is one such modalities in which the patient is undergoing immersive sessions in which they interact with an Avatar representing their main persistent auditory verbal hallucination. The aim of this study is to identify the most prevalent dyadic interactions between the patient and the Avatar in AT for patient's suffering from TRS. (2) Methods: A content analysis of 256 verbatims originating from 32 patients who completed AT between 2017 and 2022 at the Institut universitaire en santé mentale de Montréal was conducted to identify dyadic interactions between the patients and their Avatar. (3) Results: Five key dyads were identified to occur on average more than 10 times for each participant during the immersive sessions across their AT: (Avatar: Reinforcement, Patient: Self-affirmation), (Avatar: Provocation, Patient: Self-affirmation), (Avatar: Coping mechanisms, Patient: Prevention), (Patient: Self-affirmation, Avatar: Reinforcement), and (Patient: Self-appraisal, Avatar: Reinforcement). (4) Conclusion: These dyads offer a first qualitative insight to the interpersonal dynamics and patient-avatar relationships taking place during AT. Future studies on the implication of such dyadic interactions with the therapeutic outcome of AT should be conducted considering the importance of dyadic relationships in psychotherapy.

Correlation between abnormal N-acetyl-aspartate levels in posterior cingulate cortex and persistent auditory verbal hallucinations in Chinese patients with chronic schizophrenia

The aim of this study was to investigate the relationship between persistent auditory verbal hallucinations (pAVHs) and N-acetyl-aspartate (NAA) levels in posterior cingulate cortex (PCC). 117 schizophrenia (SCZ) patients (61 pAVHs and 56 non-AVHs) and 66 healthy controls were included. The P3 item of the Positive and Negative Syndrome Scale and the Auditory Hallucinations subscale of the Psychotic Symptom Rating Scale were used to assess the severity of pAVHs. NAA levels were significantly lower in the AVHs group, and were negatively correlated with pAVHs. Therefore, increasing the NAA levels in PCC may be helpful in treating pAVHs.

Implementation of a machine learning algorithm for automated thematic annotations in avatar: A linear support vector classifier approach.

Avatar Therapy (AT) is a modern therapeutic alternative for patients with schizophrenia suffering from persistent auditory verbal hallucinations. Its intrinsic therapeutical process is currently qualitatively analyzed via human coders that annotate session transcripts. This process is time and resource demanding. This creates a need to find potential algorithms that can operate on small datasets and perform such annotations. The first objective of this study is to conduct the automated text classification of interactions in AT and the second objective is to assess if this classification is comparable to the classification done by human coders. A Linear Support Vector Classifier was implemented to perform automated theme classifications on Avatar Therapy session transcripts with the use of a limited dataset with an accuracy of 66.02% and substantial classification agreement of 0.647. These results open the door to additional research such as predicting the outcome of a therapy.

The CHALLENGE trial: the effects of a virtual reality-assisted exposure therapy for persistent auditory hallucinations versus supportive counselling in people with psychosis: study protocol for a randomised clinical trial

BackgroundMany patients suffering from schizophrenia spectrum disorders continue having distressing auditory hallucinations in spite of treatment with antipsychotic medication. The aim of this trial is to examine the effect of a targeted virtual reality therapy for persistent auditory hallucinations in individuals with psychosis. The trial explores whether this type of therapy can decrease the severity, frequency and distress of auditory hallucinations and, additionally, whether it can reduce clinical symptoms and enhance daily functioning in individuals with psychosis.MethodsThe study is a randomised, assessor-blinded parallel-group superiority clinical trial, allocating a total of 266 patients to either the experimental intervention or supportive counselling. The participants will be randomised to either (1) seven sessions of virtual reality therapy or (2) seven sessions of supportive counselling to be delivered within the first 12 weeks after inclusion in the study. All participants will be assessed at baseline and 12 and 24 weeks post-baseline. Independent assessors blinded to the treatment allocation will evaluate the outcome. The primary outcome is the level of auditory hallucinations measured with the Psychotic Symptoms Rating Scales (PSYRATS-AH) total score at the cessation of treatment at 12 weeks. Secondary outcomes are frequency of auditory hallucinations, the distress caused by auditory hallucinations, perceived voice power, patient acceptance of voices, patients’ ability to respond to voices in an assertive way and social and daily function.DiscussionPromising evidence of the efficacy of this immersive virtual reality-based therapy for auditory hallucinations exist, but evidence needs to be established in a large, methodological rigorous trial. If the therapy proves to be beneficial in reducing the severity of refractory auditory hallucinations, a large group of patients with schizophrenia and related disorders could be the target group of this short-term psychotherapeutic intervention.

Superior temporal gyrus functional connectivity predicts transcranial direct current stimulation response in Schizophrenia: A machine learning study.

Transcranial direct current stimulation (tDCS) is a promising adjuvant treatment for persistent auditory verbal hallucinations (AVH) in Schizophrenia (SZ). Nonetheless, there is considerable inter-patient variability in the treatment response of AVH to tDCS in SZ. Machine-learned models have the potential to predict clinical response to tDCS in SZ. This study aims to examine the feasibility of identifying SZ patients with persistent AVH (SZ-AVH) who will respond to tDCS based on resting-state functional connectivity (rs-FC). Thirty-four SZ-AVH patients underwent resting-state functional MRI at baseline followed by add-on, twice-daily, 20-min sessions with tDCS (conventional/high-definition) for 5 days. A machine learning model was developed to identify tDCS treatment responders based on the rs-FC pattern, using the left superior temporal gyrus (LSTG) as the seed region. Functional connectivity between LSTG and brain regions involved in auditory and sensorimotor processing emerged as the important predictors of the tDCS treatment response. L1-regularized logistic regression model had an overall accuracy of 72.5% in classifying responders vs. non-responders. This model outperformed the state-of-the-art convolutional neural networks (CNN) model—both without (59.41%) and with pre-training (68.82%). It also outperformed the L1-logistic regression model trained with baseline demographic features and clinical scores of SZ patients. This study reports the first evidence that rs-fMRI-derived brain connectivity pattern can predict the clinical response of persistent AVH to add-on tDCS in SZ patients with 72.5% accuracy.

The UK AVATAR 1 and 2 Trials for People with Distressing Voices – Findings and Learning from AVATAR1, and AVATAR2 Developments in Theory and Therapy

IntroductionMany people suffering from psychotic disorders report persistent auditory verbal hallucinations (‘voices’) despite pharmacological and psychological therapy. Interest is growing in approaches that emphasise the personal relationship between the patient and their voice(s). AVATAR therapy is one such approach that uses a digital representation (avatar) of a selected voice to facilitate a three-way discussion between patient, therapist and voice, the therapist speaking either as him/herself or in the digitally transformed voice of the avatar. Objectives: To describe AVATAR therapy and an ongoing multi-centre clinical trial. Methods: Encouraging findings from an earlier controlled trial (AVATAR1) comparing AVATAR therapy and supportive counselling informed our current multi-site cost-effectiveness trial of brief and extended versions of the therapy compared to treatment as usual (AVATAR2). Results: AVATAR1 delivered in 7 weekly sessions resulted in a reduction in the frequency, distress and power of voices that was significantly superior to supportive counselling. Clinical experience suggested that some participants improved in response to the early focus on anxiety while others seemed more responsive to later more formulation-driven approach. These findings led us to the current ongoing three arm clinical trial comprising a brief (6 session) focus on anxiety/assertiveness, an extended (12 session) formulation-driven approach both approaches compared to treatment as usual. Conclusion: Previous AVATAR studies suggest this is a therapy with considerable promise. It can be delivered through widely available laptop computers, usually in clinic but also remotely via existing commercial platforms. The current trial will address questions about dissemination, training and cost-effectiveness in NHS settings.DisclosureThe digital technology employed in AVATAR therapy is provided by licence for the trial from Avatar Therapy Ltd

Metabolite differences in the medial prefrontal cortex in schizophrenia patients with and without persistent auditory verbal hallucinations: a 1H MRS study

Studies of schizophrenia (SCZ) have associated auditory verbal hallucinations (AVH) with structural and functional abnormalities in frontal cortex, especially medial prefrontal cortex (mPFC). Although abnormal prefrontal network connectivity associated with language production has been studied extensively, the relationship between mPFC dysfunction (highly relevant to the pathophysiology of SCZ) and AVH has been rarely investigated. In this study, proton magnetic resonance spectroscopy was used to measure metabolite levels in the mPFC in 61 SCZ patients with persistent AVH (pAVH), 53 SCZ patients without AVH (non-AVH), and 59 healthy controls (HC). The pAVH group showed significantly lower levels of N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (tNAA) and glutamate + glutamine (Glx), compared with the non-AVH (tNAA: p = 0.022, Glx: p = 0.012) and HC (tNAA: p = 0.001, Glx: p = 0.001) groups. No difference was found in the levels of tNAA and Glx between non-AVH and HC. The levels of tNAA and Glx in the mPFC was negatively correlated with the severity of pAVH (tNAA: r = −0.24, p = 0.014; Glx: r = −0.30, p = 0.002). In conclusion, pAVH in SCZ patients might be related to decreased levels of tNAA and Glx in the mPFC, indicating that tNAA or Glx might play a key role in the pathogenesis of pAVH.

Alterations in the volume of thalamic nuclei in patients with schizophrenia and persistent auditory hallucinations

The thalamus is a subcortical structure formed by different nuclei that relay information to the neocortex. Several reports have already described alterations of this structure in patients of schizophrenia that experience auditory hallucinations. However, to date no study has addressed whether the volumes of specific thalamic nuclei are altered in chronic patients experiencing persistent auditory hallucinations. We have processed structural MRI images using Freesurfer, and have segmented them into 25 nuclei using the probabilistic atlas developed by Iglesias and collaborators (Iglesias et al., 2018). To homogenize the sample, we have matched patients of schizophrenia, with and without persistent auditory hallucinations, with control subjects, considering sex, age and their estimated intracranial volume. This rendered a group number of 41 patients experiencing persistent auditory hallucinations, 35 patients without auditory hallucinations, and 55 healthy controls. In addition, we have also correlated the volume of the altered thalamic nuclei with the total score of the PSYRATS, a clinical scale used to evaluate the positive symptoms of this disorder. We have found alterations in the volume of 8 thalamic nuclei in both cohorts of patients with schizophrenia: The medial and lateral geniculate nuclei, the anterior, inferior, and lateral pulvinar nuclei, the lateral complex and the lateral and medial mediodorsal nuclei. We have also found some significant correlations between the volume of these nuclei in patients experiencing auditory hallucinations, and the total score of the PSYRATS scale. Altogether our results indicate that volumetric alterations of thalamic nuclei involved in audition may be related to persistent auditory hallucinations in chronic schizophrenia patients, whereas alterations in nuclei related to association cortices are evident in all patients. Future studies should explore whether the structural alterations are cause or consequence of these positive symptoms and whether they are already present in first episodes of psychosis.

Alterations in the volume of thalamic nuclei in patients with schizophrenia and persistent auditory hallucinations

Alterations in the volume of thalamic nuclei in patients with schizophrenia and persistent auditory hallucinations

Cessation of clozapine-induced severe hypersalivation along with improvement of residual persistent auditory hallucinations by tDCS in a patient of chronic schizophrenia - A case report.

Sir, A 47-year-old male, case of treatment-resistant schizophrenia, had presented with refractory auditory hallucinations, delusion of persecution, and reference at our center. The patient had a continuous progressive illness of 20 years with good compliance to treatment. Initially, he had positive symptoms such as thought broadcast, delusion of persecution, and derogatory auditory hallucinations. In the course of treatment, the symptoms responded with medications and ECT. However, the auditory hallucinations remained refractory to treatment. In 2010, the patient was started on clozapine, which was gradually escalated up to 450 mg. In 2016, haloperidol was added for augmentation, still the hallucinations persisted. Hypersalivation was noted ever since the patient was started on clozapine. Glycopyrrolate (4 mg) was added for the same; however, minimal improvement was noted. In 2020, when the patient was taken for tDCS therapy in view of refractory auditory hallucinations, he was already on clozapine (450 mg) and glycopyrrolate (4 mg). The patient received tDCS sessions on an outpatient basis after taking informed consent. The target areas of stimulation were left temporoparietal junction as the cathode and right dorsolateral prefrontal cortex as the anode. The intensity was kept at 2 mA and stimulation was given for 30 minutes once daily on weekdays. At the end of 15 sessions, there was a significant decline in PANSS scores (composite score reduced from 11 to 3) along with a near-complete cessation of auditory hallucinations. It was observed that not only hallucinations but hypersalivation also improved significantly. Even in the follow-up visits, hypersalivation did not remain a major concern as previously. However, the patient continued to take 4 mg of glycopyrrolate. DISCUSSION The causes of hypersalivation, a distressing side effect that occurs in 31%–54% of patients receiving clozapine therapy, are nonspecific.[1] It may be mediated by the imbalance between M3 receptor blockade (decrease in salivation) and M4 receptor stimulation (increase in salivary output). Another explanation is that clozapine interferes with the swallowing reflex, leading to the pooling of saliva and, therefore, patient complaints of hypersalivation.[2] tDCS administered to the hyperactive left temporoparietal junction (“inhibitory” cathodal) and to the hypoactive left dorsolateral prefrontal cortex (“excitatory” anodal) improves refractory hallucinations as studied earlier.[3] However, the action of tDCS on clozapine-induced hypersalivation has not been noted earlier. It has also been reported that anodal tDCS projecting to the swallowing sensorimotor cortical acts on cricopharyngeal muscles and improves swallowing.[4] Bihemispheric anodal tDCS has been applied to better modulate the excitability of esophageal cortex (proximal to pharyngeal cortex) and improve dysphagia.[5] Nitsche etal.[6] have also stated that tDCS mediates increase in catecholamine through neuroplastic changes. The above-mentioned theories could possibly explain the improvement in hypersalivation in this case. CONCLUSION Although no direct association of tDCS on clozapine-induced hypersalivation has been observed or reported earlier, the above case suggests a temporal correlation between the two. Effect of tDCS through its action on pharyngeal musculature or by catecholaminergic changes could be a topic of further research. tDCS could also be used as an adjunct to pharmacotherapy in treating clozapine-induced hypersalivation. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

A Review of Studies Leveraging Multimodal TMS-fMRI Applications in the Pathophysiology and Treatment of Schizophrenia.

The current review provides an overview of the existing literature on multimodal transcranial magnetic stimulation, and functional magnetic resonance imaging (TMS/fMRI) studies in individuals with schizophrenia and discusses potential future avenues related to the same. Multimodal studies investigating pathophysiology have explored the role of abnormal thalamic reactivity and have provided further evidence supporting the hypothesis of schizophrenia as a disorder of aberrant connectivity and cortical plasticity. Among studies examining treatment, low-frequency rTMS for the management of persistent auditory verbal hallucinations (AVH) was the most studied. While multimodal TMS/fMRI studies have provided evidence of involvement of local speech-related and distal networks on stimulation of the left temporoparietal cortex, current evidence does not suggest the superiority of fMRI based neuronavigation over conventional methods or of active rTMS over sham for treatment of AVH. Apart from these, preliminary findings suggest a role of rTMS in treating deficits in neurocognition, social cognition, and self-agency. However, most of these studies have only examined medication-resistant symptoms and have methodological concerns arising from small sample sizes and short treatment protocols. That being said, combining TMS with fMRI appears to be a promising approach toward elucidating the pathophysiology of schizophrenia and could also open up a possibility toward developing personalized treatment for its persistent and debilitating symptoms.

Cyclical Premenstrual Psychosis - Sometimes It Is Your Hormones

Background: Menstrual psychosis is a broad term used to describe a number of disorders characterized by the acute onset of psychotic symptoms with brief duration, complete resolution of symptoms between episodes, with timing related to menses. This entity was first described in the 18th century, with only 27 confirmed cases using strict diagnostic criteria. While research into causation is limited, estrogen withdrawal is thought to precipitate psychotic symptoms. We describe a case of premenstrual psychosis successfully treated with use of transdermal hormonal contraception and extended menstrual cycling. Clinical Case: A 25-year-old non-binary biologic female (they/them/theirs) with bipolar disorder, anxiety, and psychogenic non-epileptiform seizures was referred to endocrinology for evaluation of recurrent psychotic symptoms associated with menses. They endorsed stable mental health symptoms on aripiprazole except during the seven days prior to their menstrual cycle. During this time they reported persistent auditory hallucinations along with dysmenorrhea, with symptoms resolving at the onset of menses. Timing of menarche was uncertain, however they reported oligomenorrhea until beginning oral contraceptives at age nineteen, after which they developed regular monthly cycles accompanied by psychotic symptoms. Pituitary and ovarian hormone levels were unable to be assessed due to hormonal contraception. Prolactin was 8.3 ng/mL (3-30 ng/mL). In order to limit hormonal fluctuations from daily oral contraceptive pills and monthly withdrawal, the decision was made to transition to transdermal norelgestromin and ethinyl estradiol patches changed weekly, with extended cycling to allow one menstrual cycle every three months. At follow-up visit nine months later they reported resolution of auditory hallucinations on this regimen, with symptoms recurring only during extreme stress. Conclusions: While the etiology of menstrual psychosis is unclear, described treatments include a combination of neuroleptics and hormonal therapy, including estrogen, progesterone, and GnRH agonists. As symptoms did not resolve until suppression of monthly menstrual cycles, this case supports the estrogen withdrawal hypothesis. Our case adds to the literature both in that transdermal, rather than oral or injectable therapy was used, and treatment was successful in alleviating the patient’s psychotic symptoms, improving their mental health and quality of life.