New-Onset Occipital Lobe Epilepsy in an Elderly Patient With Visual Hallucinations and Hemianopia.

Occipital lobe epilepsies (OLEs) are a subset of epileptic disorders manifesting predominantly with visual and oculomotor abnormalities that are often misdiagnosed due to similarities with migraines with visual aura and other central nervous system (CNS) pathologies. This case study describes an 88-year-old male with a three-week history of intermittent kaleidoscopic visual phenomena, accompanied by blurring of vision and altered level of consciousness. Neurological examination revealed right homonymous hemianopsia and focal neurological deficits, including forced right gaze preference and nystagmus. Diagnostic modalities, MRI and MRA, ruled out ischemic stroke but indicated mild to moderate cerebral atrophy and chronic microvascular ischemic changes. The patient exhibited a seizure episode characterized by right-sided gaze preference and altered consciousness. Postictally, transient right homonymous hemianopsia was observed, consistent with Todd's phenomenon. Treatment with intravenous levetiracetam and lorazepam led to a reduction in seizure frequency. This case highlights the importance of comprehensive evaluation in distinguishing OLEs from other conditions with similar visual presentations like migraine with aura or occipital lobe stroke being more predominant.

Prevalence of psychotic symptoms in mild cognitive impairment: A systematic review and meta-analysis.

INTRODUCTION: Neuropsychiatric symptoms may impact prognosis in individuals with mild cognitive impairment (MCI); however, data on frequency of psychotic symptoms are sparse. METHODS: We searched MEDLINE, EMBASE, PsychoINFO from inception to June 2023. We included studies reporting patients with MCI prevalence of (delusions and/or hallucinations. Random effects model were performed to estimate the prevalence, and subgroup and meta-regression analyses were performed to explore heterogeneity. RESULTS: Of 3145 records identified, 36 studies were included, enrolling 20,426 patients. Overall prevalence of hallucinations was 1.78 % (95 % CI, 1.17 - 2.71) and delusions 3.84 % (95 % CI, 2.71 - 5.42), both with significant heterogeneity (/2 = 90 %). Prevalence of hallucinations and delusions were lower when measured by NPI scales and in population-based samples. DISCUSSION: Delusions and hallucinations occur in MCI patients at low rates. Prevalence can be partially explained by the assessment method, sample source and study heterogeneity.

Severe Dissociative Experiences beyond Detachment in a Large Clinical Sample of Inpatients with Post-Traumatic Stress Disorder: Diagnostic and Treatment Implications.

INTRODUCTION: The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) contains a dissociative subtype of post-traumatic stress disorder (PTSD) characterized by depersonalization and derealization. Yet, there is evidence that dissociative symptoms in PTSD go beyond this kind of detachment dissociation and that some patients present with additional compartmentalization dissociation in the form of auditory-verbal hallucination, amnesia, and identity alteration. METHODS: Hence, in this study, we examined latent profiles of childhood trauma (Childhood Trauma Questionnaire), PTSD (Impact-of-Event Scale-Revised), and pathological dissociation (Dissociative Experiences Scale-Taxon; DES-T) in a large sample of severely traumatized inpatients with PTSD (N = 1,360). RESULTS: Results support a three-class solution of the latent profile analysis with a PTSD class, a dissociative subtype class, and a third class characterized by more complex and more severe dissociative symptoms. Importantly, in our inpatient sample of patients with severe PTSD, the latter class was found to be the most prevalent. Both the exploratory character of our retrospective analysis of clinical routine data and the use of the DES-T limit the generalizability of our findings, which require methodologically more rigorous replication. CONCLUSION: In severe PTSD, dissociative symptoms beyond detachment are highly prevalent. Diagnostic and treatment implications are discussed.

Hallucinations and Vitamin B12 Deficiency: A Systematic Review.

INTRODUCTION: Vitamin B12 deficiency is primarily associated with pernicious anaemia, polyneuropathy, and spinal-cord disease, but publications on its association with hallucinations are on the rise. METHODS: I carried out a systematic literature search on these hallucinations in PubMed, PsycINFO, and Google Scholar, up until July 1, 2023. RESULTS: The search yielded 50 case studies published between 1960 and 2023. The hallucinations described therein are predominantly visual and/or auditory in nature, with 20% being specified as complex, compound, or panoramic. They are often described in the context of vitamin B12-related neuropsychiatric conditions such as dementia, delirium, epilepsy, psychotic disorder, schizoaffective disorder, bipolar disorder, depressive disorder, catatonia, or obsessive-compulsive disorder. In the context of such disorders, they tend to appear first and also often appear to be the first to disappear with cobalamin treatment. Within an average of 2 months, full amelioration was thus obtained in 75% of the cases and partial amelioration in the remaining 25%. Remarkably, a quarter of the cases involved therapy-resistant hallucinations that fully resolved under cobalamin monotherapy, while other neuropsychiatric manifestations of vitamin B12 deficiency disappeared in 60% of the treated cases. Only 32% of the cases involved comorbid pernicious anaemia. This suggests that two separate or diverging pathways exist for perceptual and haematological symptoms of vitamin B12 deficiency. CONCLUSION: In the light of the high prevalence rate of vitamin B12 deficiency in the general population, the findings here presented should be interpreted with great caution. Nonetheless, they offer cues for further research and experimental application in clinical practice. This may be especially relevant in light of the recent increase in the popularity of vegetarianism and the recreational use of nitrous oxide (laughing gas), which are both risk factors for vitamin B12 deficiency.

Episodic Visual Hallucinations, Inference and Free Energy.

Understandings of how visual hallucinations appear have been highly influenced by generative approaches, in particular Friston's Active Inference conceptualization. Their core proposition is that these phenomena occur when hallucinatory expectations outweigh actual sensory data. This imbalance occurs as the brain seeks to minimize informational free energy, a measure of the distance between predicted and actual sensory data in a stationary open system. We review this approach in the light of old and new information on the role of environmental factors in episodic hallucinations. In particular, we highlight the possible relationship of specific visual triggers to the onset and offset of some episodes. We use an analogy from phase transitions in physics to explore factors which might account for intermittent shifts between veridical and hallucinatory vision. In these triggered forms of hallucinations, we suggest that there is a transient disturbance in the normal one-to-one correspondence between a real object and the counterpart perception such that this correspondence becomes between the real object and a hallucination. Generative models propose that a lack of information transfer from the environment to the brain is one of the key features of hallucinations. In contrast, we submit that specific information transfer is required at onset and offset in these cases. We propose that this transient one-to-one correspondence between environment and hallucination is mediated more by aberrant discriminative than by generative inference. Discriminative inference can be conceptualized as a process for maximizing shared information between the environment and perception within a self-organizing nonstationary system. We suggest that generative inference plays the greater role in established hallucinations and in the persistence of individual hallucinatory episodes. We further explore whether thermodynamic free energy may be an additional factor in why hallucinations are temporary. Future empirical research could productively concentrate on three areas. Firstly, subjective perceptual changes and parallel variations in brain function during specific transitions between veridical and hallucinatory vision to inform models of how episodes occur. Secondly, systematic investigation of the links between environment and hallucination episodes to probe the role of information transfer in triggering transitions between veridical and hallucinatory vision. Finally, changes in hallucinatory episodes over time to elucidate the role of learning on phenomenology. These empirical data will allow the potential roles of different forms of inference in the stages of hallucinatory episodes to be elucidated.

Aberrant Hippocampal Neuroregenerative Plasticity in Schizophrenia: Reactive Neuroblastosis as a Possible Pathocellular Mechanism of Hallucination.

Hallucination is a sensory perception that occurs in the absence of external stimuli during abnormal neurological disturbances and various mental diseases. Hallucination is recognized as a core psychotic symptom and is particularly more prevalent in individuals with schizophrenia. Strikingly, a significant number of subjects with Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other neurological diseases like cerebral stroke and epileptic seizure also experience hallucination. While aberrant neurotransmission has been linked to the neuropathogenic events of schizophrenia, the precise cellular mechanism accounting for hallucinations remains obscure. Neurogenesis is a cellular process of producing new neurons from the neural stem cells (NSC)-derived neuroblasts in the brain that contribute to the regulation of pattern separation, mood, olfaction, learning, and memory in adulthood. Impaired neurogenesis in the hippocampus of the adult brain has been linked to stress, anxiety, depression, and dementia. Notably, many neurodegenerative disorders are characterized by the mitotic and functional activation of neuroblasts and cell cycle re-entry of mature neurons leading to a drastic alteration in neurogenic process, known as reactive neuroblastosis. Considering their neurophysiological properties, the abnormal integration of neuroblasts into the existing neural network or withdrawal of their connections can lead to abnormal synaptogenesis, and neurotransmission. Eventually, this would be expected to result in altered perception accounting for hallucination. Thus, this article emphasizes a hypothesis that aberrant neurogenic processes at the level of reactive neuroblastosis could be an underlying mechanism of hallucination in schizophrenia and other neurological diseases.

Variability in white matter structure relates to hallucination proneness.

Hallucinations are a prominent transdiagnostic psychiatric symptom but are also prevalent in individuals who do not require clinical care. Moreover, persistent psychosis-like experience in otherwise healthy individuals may be related to an increased risk to transition to a psychotic disorder. This suggests a common etiology across clinical and non-clinical individuals along a multidimensional psychosis continuum that may be detectable in structural variations of the brain. The current diffusion tensor imaging study assessed 50 healthy individuals (35 females) to identify possible differences in white matter associated with hallucination proneness (HP). This approach circumvents potential confounds related to medication, hospitalization, and disease progression common in clinical individuals. We determined how HP relates to white matter structure in selected association, commissural, and projection fiber pathways putatively linked to psychosis. Increased HP was associated with enhanced fractional anisotropy (FA) in the right uncinate fasciculus, the right anterior and posterior arcuate fasciculus, and the corpus callosum. These findings support the notion of a psychosis continuum, providing first evidence of structural white matter variability associated with HP in healthy individuals. Furthermore, alterations in the targeted pathways likely indicate an association between HP-related structural variations and the putative salience and attention mechanisms that these pathways subserve.

Reference Hallucination Score for Medical Artificial Intelligence Chatbots: Development and Usability Study.

BACKGROUND: Artificial intelligence (AI) chatbots have recently gained use in medical practice by health care practitioners. Interestingly, the output of these AI chatbots was found to have varying degrees of hallucination in content and references. Such hallucinations generate doubts about their output and their implementation. OBJECTIVE: The aim of our study was to propose a reference hallucination score (RHS) to evaluate the authenticity of AI chatbots' citations. METHODS: Six AI chatbots were challenged with the same 10 medical prompts, requesting 10 references per prompt. The RHS is composed of 6 bibliographic items and the reference's relevance to prompts' keywords. RHS was calculated for each reference, prompt, and type of prompt (basic vs complex). The average RHS was calculated for each AI chatbot and compared across the different types of prompts and AI chatbots. RESULTS: Bard failed to generate any references. ChatGPT 3.5 and Bing generated the highest RHS (score=11), while Elicit and SciSpace generated the lowest RHS (score=1), and Perplexity generated a middle RHS (score=7). The highest degree of hallucination was observed for reference relevancy to the prompt keywords (308/500, 61.6%), while the lowest was for reference titles (169/500, 33.8%). ChatGPT and Bing had comparable RHS (ß coefficient=-0.069; P=.32), while Perplexity had significantly lower RHS than ChatGPT (ß coefficient=-0.345; P<.001). AI chatbots generally had significantly higher RHS when prompted with scenarios or complex format prompts (ß coefficient=0.486; P<.001). CONCLUSIONS: The variation in RHS underscores the necessity for a robust reference evaluation tool to improve the authenticity of AI chatbots. Further, the variations highlight the importance of verifying their output and citations. Elicit and SciSpace had negligible hallucination, while ChatGPT and Bing had critical hallucination levels. The proposed AI chatbots' RHS could contribute to ongoing efforts to enhance AI's general reliability in medical research.

Consciousness in non-REM-parasomnia episodes.

Sleepwalking and related parasomnias are thought to result from incomplete awakenings out of non-rapid eye movement (non-REM) sleep. Non-REM parasomnia behaviours have been described as unconscious and automatic, or related to vivid, dream-like conscious experiences. Similarly, some observations have suggested that patients are unresponsive during episodes, while others that they can interact with their surroundings. To better grasp and characterise the full spectrum of consciousness and environmental (dis)connection associated with behavioural episodes, 35 adult patients with non-REM sleep parasomnias were interviewed in-depth about their experiences. The level of consciousness during parasomnia episodes was reported to be variable both within and between individuals, ranging from minimal or absent consciousness and largely automatic behaviours (frequently/always present in 36% of patients) to preserved conscious experiences characterised by delusional thinking to varying degrees of specificity (65%), often about impending danger, variably formed, uni- or multisensory hallucinations (53%), impaired insight (77%), negative emotions (75%), and variable, but often pronounced, amnesia (30%). Patients described their experiences as a dream scene during which they felt awake ("awake dreaming"). The surroundings were either realistically perceived, misinterpreted (in the form of perceptual illusions or misidentifications of people), or entirely hallucinated as a function of the prevailing delusion. These observations suggest that the level of consciousness, amnesia and sensory disconnection during non-REM parasomnia episodes is variable and graded. In their full-fledged expression, non-REM parasomnia experiences feature several core features of dreams. They therefore represent a valuable model for the study of consciousness, sleep-related sensory disconnection and dreaming.

Patient-centered radiology reports with generative artificial intelligence: adding value to radiology reporting.

The purposes were to assess the efficacy of AI-generated radiology reports in terms of report summary, patient-friendliness, and recommendations and to evaluate the consistent performance of report quality and accuracy, contributing to the advancement of radiology workflow. Total 685 spine MRI reports were retrieved from our hospital database. AI-generated radiology reports were generated in three formats: (1) summary reports, (2) patient-friendly reports, and (3) recommendations. The occurrence of artificial hallucinations was evaluated in the AI-generated reports. Two radiologists conducted qualitative and quantitative assessments considering the original report as a standard reference. Two non-physician raters assessed their understanding of the content of original and patient-friendly reports using a 5-point Likert scale. The scoring of the AI-generated radiology reports were overall high average scores across all three formats. The average comprehension score for the original report was 2.71 ± 0.73, while the score for the patient-friendly reports significantly increased to 4.69 ± 0.48 (p < 0.001). There were 1.12% artificial hallucinations and 7.40% potentially harmful translations. In conclusion, the potential benefits of using generative AI assistants to generate these reports include improved report quality, greater efficiency in radiology workflow for producing summaries, patient-centered reports, and recommendations, and a move toward patient-centered radiology.

Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS).

Background: Mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) is increasingly recognized as a clinicoradiological syndrome. Its etiology is diverse, encompassing a variety of triggers, including infections and metabolic abnormalities. Uniquely, MERS may present with psychiatric symptoms, such as delirium, visual hallucinations, and catatonia, posing diagnostic challenges. The variability of these neuropsychiatric symptoms necessitates early diagnosis through magnetic resonance imaging (MRI) to avoid prolonged antipsychotic treatment. Case Presentation: This report details a case of MERS in a 39-year-old male. The patient initially presented with headache, sore throat, and abnormal laboratory results: leukocytosis, neutrophilia with a left shift, elevated C-reactive protein (CRP) levels, and hyponatremia. On the fourth day of admission, he developed severe anxiety and restlessness, exhibited thoughts of death, and reported experiencing vivid hallucinations upon closing his eyes. MRI revealed a hyperintense lesion in the corpus callosum. A lumbar puncture showed no increase in cell count or protein. The patient showed a positive response to treatment with antibiotics and olanzapine, demonstrating rapid symptomatic improvement. A follow-up MRI on the 11th day showed complete resolution of the brain lesions. Six months later, no neurological or psychiatric sequelae were noted. The patient's clinical progression and imaging findings led to a definitive diagnosis of MERS. Conclusion: The early presentation of symptoms such as restlessness, hallucinations, and death ideation played a critical role in diagnosing MERS, with early MRI examination being instrumental in both diagnosis and preventing prolonged antipsychotic medication use.

Cortical determinants of loudness perception and auditory hypersensitivity.

Parvalbumin-expressing inhibitory neurons (PVNs) stabilize cortical network activity, generate gamma rhythms, and regulate experience-dependent plasticity. Here, we observed that activation or inactivation of PVNs functioned like a volume knob in the mouse auditory cortex (ACtx), turning neural and behavioral classification of sound level up or down over a 20dB range. PVN loudness adjustments were "sticky", such that a single bout of 40Hz PVN stimulation sustainably suppressed ACtx sound responsiveness, potentiated feedforward inhibition, and behaviorally desensitized mice to loudness. Sensory sensitivity is a cardinal feature of autism, aging, and peripheral neuropathy, prompting us to ask whether PVN stimulation can persistently desensitize mice with ACtx hyperactivity, PVN hypofunction, and loudness hypersensitivity triggered by cochlear sensorineural damage. We found that a single 16-minute bout of 40Hz PVN stimulation session restored normal loudness perception for one week, showing that perceptual deficits triggered by irreversible peripheral injuries can be reversed through targeted cortical circuit interventions.

Association between cannabis potency and mental health in adolescence.

INTRODUCTION: In legal and illegal markets, high-potency cannabis (>10 % delta-9-tetrahydrocannabinol (THC)) is increasingly available. In adult samples higher-potency cannabis has been associated with mental health disorder but no studies have considered associations in adolescence. METHODS: A population-wide study compared no, low and high potency cannabis using adolescents (aged 13-14 years) self-reported symptoms of probable depression, anxiety, and auditory hallucinations. RESULTS: Of the 6672 participants, high-potency cannabis was used by 2.6 % (n=171) and low-potency by 0.6 % (n=38). After adjustment for sociodemographic factors, tobacco and alcohol use, in comparison to participants who had never used cannabis, people who had used high-potency but not low-potency cannabis were more likely to report symptoms of depression (odds ratio 1.59 [95 % confidence interval 1.06, 2.39), anxiety (OR 1.45, 95 % CI 0.96, 2.20), and auditory hallucinations (OR 1.56, 95 % CI 0.98, 2.47). CONCLUSIONS: High-potency cannabis use is associated with an increased risk of probable mental health disorders. Services and programming to minimise drug harms may need to be adapted to pay more attention to cannabis potency.

Hallucination Proneness Alters Sensory Feedback Processing in Self-voice Production.

BACKGROUND: Sensory suppression occurs when hearing one's self-generated voice, as opposed to passively listening to one's own voice. Quality changes in sensory feedback to the self-generated voice can increase attentional control. These changes affect the self-other voice distinction and might lead to hearing voices in the absence of an external source (ie, auditory verbal hallucinations). However, it is unclear how changes in sensory feedback processing and attention allocation interact and how this interaction might relate to hallucination proneness (HP). STUDY DESIGN: Participants varying in HP self-generated (via a button-press) and passively listened to their voice that varied in emotional quality and certainty of recognition-100% neutral, 60%-40% neutral-angry, 50%-50% neutral-angry, 40%-60% neutral-angry, 100% angry, during electroencephalography (EEG) recordings. STUDY RESULTS: The N1 auditory evoked potential was more suppressed for self-generated than externally generated voices. Increased HP was associated with (1) an increased N1 response to the self- compared with externally generated voices, (2) a reduced N1 response for angry compared with neutral voices, and (3) a reduced N2 response to unexpected voice quality in sensory feedback (60%-40% neutral-angry) compared with neutral voices. CONCLUSIONS: The current study highlights an association between increased HP and systematic changes in the emotional quality and certainty in sensory feedback processing (N1) and attentional control (N2) in self-voice production in a nonclinical population. Considering that voice hearers also display these changes, these findings support the continuum hypothesis.

Large language models in psychiatry: Opportunities and challenges.

The ability of Large Language Models (LLMs) to analyze and respond to freely written text is causing increasing excitement in the field of psychiatry; the application of such models presents unique opportunities and challenges for psychiatric applications. This review article seeks to offer a comprehensive overview of LLMs in psychiatry, their model architecture, potential use cases, and clinical considerations. LLM frameworks such as ChatGPT/GPT-4 are trained on huge amounts of text data that are sometimes fine-tuned for specific tasks. This opens up a wide range of possible psychiatric applications, such as accurately predicting individual patient risk factors for specific disorders, engaging in therapeutic intervention, and analyzing therapeutic material, to name a few. However, adoption in the psychiatric setting presents many challenges, including inherent limitations and biases in LLMs, concerns about explainability and privacy, and the potential damage resulting from produced misinformation. This review covers potential opportunities and limitations and highlights potential considerations when these models are applied in a real-world psychiatric context.

Drug-induced musical hallucination.

Musical hallucination is a rare perceptual phenomenon wherein individuals hear music in the absence of external auditory stimuli. This phenomenon occurs across diverse medical conditions and can be triggered by some drugs. The underlying mechanism of drug-induced hallucination is unknown. This study explores drug-induced musical hallucination through a literature review, aiming to investigate its pathophysiology and potential treatment modalities. A literature search was conducted until January 2024 using databases PubMed, WorldCat, Google Scholar, and DOAJ, with keywords "drugs induced musical hallucination" or "drugs" combined with "musical hallucination." The search yielded 24 articles which met inclusion criteria, encompassing 27 cases. The average patient age was 58.3 years, with 67.9% females. Prevalent conditions among cases included hearing impairments, psychiatric disorders, cancers, and neurodegenerative conditions. Common trigger drugs comprised antidepressants, opioids, anti-Parkinson drugs, ketamine, and voriconazole. Musical hallucination descriptions varied widely, and 6 patients reported concurrent visual hallucinations. The onset of symptoms ranged from 75 min to 240 days. Treatment strategies included termination of trigger drugs, dosage reduction, alteration of administration routes or formula, switching to similar drugs, or addition of antidepressants, sedatives, or atypical antipsychotic medications. Musical hallucinations completely disappeared in 24/27 (88.9%) patients but continued in 3/27 (11.1%) patients. The current study concludes that drug-induced musical hallucination may arise from altering neurotransmitter/receptor balance and intricate interactions between trigger drugs and underlying conditions.

Association between voriconazole-induced visual hallucination and dopamine in an analysis of the food and drug administration (FDA) adverse event reporting system database.

Voriconazole is a second-generation azole used to treat serious fungal infections. Visual hallucinations constitute a representative adverse event caused by voriconazole. However, its mechanism of action remains unclear. In patients with schizophrenia or Parkinson's disease, the frequency of visual hallucinations is associated with brain dopamine levels. This study investigated the frequency of visual hallucinations in patients treated with voriconazole alone or in combination with dopaminergic medicines or dopamine antagonists, using data collected from the Food and Drug Administration Adverse event Reporting System (FAERS). The frequency of visual hallucinations with voriconazole alone and in combination with a dopaminergic medicine (levodopa) or dopamine antagonists (risperidone and chlorpromazine) was compared using data from the FAERS between 2004 and 2023, using the reporting odds ratio (ROR) with relevant 95% confidence intervals (CI). The reference group comprised patients who had been administered voriconazole without dopaminergic medication or dopamine antagonists. Of the patients, 22,839, 90,810, 109,757, 6,435, 20, 83, and 26, respectively were treated with voriconazole, levodopa, risperidone, chlorpromazine, voriconazole plus levodopa, voriconazole plus risperidone, and voriconazole plus chlorpromazine. The occurrence of visual hallucinations increased when used in combination with levodopa (ROR = 12.302, 95% CI = 3.587-42.183). No increase in incidence was associated with the concomitant use of dopamine antagonists (risperidone, ROR = 1.721, 95% CI = 0.421-7.030; chlorpromazine, ROR = none, 95% CI = none). Dopaminergic medicine may increase the risk of visual hallucinations in patients treated with voriconazole. Whether voriconazole positively modulates dopamine production warrants further investigation using a translational research approach.

An attentional and working memory theory of hallucination vulnerability in frontotemporal dementia.

The rate and prevalence of hallucinations in behavioural variant frontotemporal dementia is well established. The mechanisms for underlying vulnerability however are the least well described in FTD compared with other neuropsychiatric conditions, despite the presence of these features significantly complicating the diagnostic process. As such, this present study aimed to provide a detailed characterization of the neural, cognitive and behavioural profile associated with a predisposition to hallucinatory experiences in behavioural variant frontotemporal dementia. In total, 153 patients with behavioural variant frontotemporal dementia were recruited sequentially for this study. A group of patients with well characterized hallucinations and good-quality volumetric MRI scans (n = 23) were genetically and demographically matched to a group without hallucinations (n = 23) and a healthy control cohort (n = 23). All patients were assessed at their initial visit by means of a detailed clinical interview, a comprehensive battery of neuropsychological tests and MRI. Data were analysed according to three levels: (i) the relationship between neural structures, cognition, behaviour and hallucinations in behavioural variant frontotemporal dementia; (ii) the impact of the C9orf72 expansion; and (iii) hallucination subtype on expression of hallucinations. Basic and complex attentional (including divided attention and working memory) and visual function measures differed between groups (all P < 0.001) with hallucinators demonstrating poorer performance, along with evidence of structural changes centred on the prefrontal cortex, caudate and cerebellum (corrected for False Discovery Rate at P < 0.05 with a cluster threshold of 100 contiguous voxels). Attentional processes were also implicated in C9orf72 carriers with hallucinations with structural changes selectively involving the thalamus. Patients with visual hallucinations in isolation showed a similar pattern with emphasis on cerebellar atrophy. Our findings provided novel insights that attentional and visual function subsystems and related distributed brain structures are implicated in the generation of hallucinations in behavioural variant frontotemporal dementia, that dissociate across C9orf72, sporadic behavioural variant frontotemporal dementia and for the visual subtype of hallucinations. This loading on attentional and working memory measures is in line with current mechanistic models of hallucinations that frequently suggest a failure of integration of cognitive and perceptual processes. We therefore propose a novel cognitive and neural model for hallucination predisposition in behavioural variant frontotemporal dementia that aligns with a transdiagnostic model for hallucinations across neurodegeneration and psychiatry.

Diversifying de novo TIM barrels by hallucination.

De novo protein design expands the protein universe by creating new sequences to accomplish tailor-made enzymes in the future. A promising topology to implement diverse enzyme functions is the ubiquitous TIM-barrel fold. Since the initial de novo design of an idealized four-fold symmetric TIM barrel, the family of de novo TIM barrels is expanding rapidly. Despite this and in contrast to natural TIM barrels, these novel proteins lack cavities and structural elements essential for the incorporation of binding sites or enzymatic functions. In this work, we diversified a de novo TIM barrel by extending multiple ßα-loops using constrained hallucination. Experimentally tested designs were found to be soluble upon expression in Escherichia coli and well-behaved. Biochemical characterization and crystal structures revealed successful extensions with defined α-helical structures. These diversified de novo TIM barrels provide a framework to explore a broad spectrum of functions based on the potential of natural TIM barrels.