The central role of the Thalamus in psychosis, lessons from neurodegenerative diseases and psychedelics.

The PD-DLB psychosis complex found in Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB) includes hallucinations, Somatic Symptom/Functional Disorders, and delusions. These disorders exhibit similar presentation patterns and progression. Mechanisms at the root of these symptoms also share similarities with processes promoting altered states of consciousness found in Rapid Eye Movement sleep, psychiatric disorders, or the intake of psychedelic compounds. We propose that these mechanisms find a crucial driver and trigger in the dysregulated activity of high-order thalamic nuclei set in motion by ThalamoCortical Dysrhythmia (TCD). TCD generates the loss of finely tuned cortico-cortical modulations promoted by the thalamus and unleashes the aberrant activity of the Default Mode Network (DMN). TCD moves in parallel with altered thalamic filtering of external and internal information. The process produces an input overload to the cortex, thereby exacerbating DMN decoupling from task-positive networks. These phenomena alter the brain metastability, creating dreamlike, dissociative, or altered states of consciousness. In support of this hypothesis, mind-altering psychedelic drugs also modulate thalamic-cortical pathways. Understanding the pathophysiological background of these conditions provides a conceptual bridge between neurology and psychiatry, thereby helping to generate a promising and converging area of investigation and therapeutic efforts.

LSD-induced changes in the functional connectivity of distinct thalamic nuclei.

The role of the thalamus in mediating the effects of lysergic acid diethylamide (LSD) was recently proposed in a model of communication and corroborated by imaging studies. However, a detailed analysis of LSD effects on nuclei-resolved thalamocortical connectivity is still missing. Here, in a group of healthy volunteers, we evaluated whether LSD intake alters the thalamocortical coupling in a nucleus-specific manner. Structural and resting-state functional Magnetic Resonance Imaging (MRI) data were acquired in a placebo-controlled study on subjects exposed to acute LSD administration. Structural MRI was used to parcel the thalamus into its constituent nuclei based on individual anatomy. Nucleus-specific changes of resting-state functional MRI (rs-fMRI) connectivity were mapped using a seed-based approach. LSD intake selectively increased the thalamocortical functional connectivity (FC) of the ventral complex, pulvinar, and non-specific nuclei. Functional coupling was increased between these nuclei and sensory cortices that include the somatosensory and auditory networks. The ventral and pulvinar nuclei also exhibited increased FC with parts of the associative cortex that are dense in serotonin type 2A receptors. These areas are hyperactive and hyper-connected upon LSD intake. At subcortical levels, LSD increased the functional coupling among the thalamus's ventral, pulvinar, and non-specific nuclei, but decreased the striatal-thalamic connectivity. These findings unravel some LSD effects on the modulation of subcortical-cortical circuits and associated behavioral outputs.

A Machine Learning-Based Holistic Approach to Predict the Clinical Course of Patients within the Alzheimer's Disease Spectrum.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative condition driven by multifactorial etiology. Mild cognitive impairment (MCI) is a transitional condition between healthy aging and dementia. No reliable biomarkers are available to predict the conversion from MCI to AD. OBJECTIVE: To evaluate the use of machine learning (ML) on a wealth of data offered by the Alzheimer's Disease Neuroimaging Initiative (ADNI) and Alzheimer's Disease Metabolomics Consortium (ADMC) database in the prediction of the MCI to AD conversion. METHODS: We implemented an ML-based Random Forest (RF) algorithm to predict conversion from MCI to AD. Data related to the study population (587 MCI subjects) were analyzed by RF as separate or combined features and assessed for classification power. Four classes of variables were considered: neuropsychological test scores, AD-related cerebrospinal fluid (CSF) biomarkers, peripheral biomarkers, and structural magnetic resonance imaging (MRI) variables. RESULTS: The ML-based algorithm exhibited 86% accuracy in predicting the AD conversion of MCI subjects. When assessing the features that helped the most, neuropsychological test scores, MRI data, and CSF biomarkers were the most relevant in the MCI to AD prediction. Peripheral parameters were effective when employed in association with neuropsychological test scores. Age and sex differences modulated the prediction accuracy. AD conversion was more effectively predicted in females and younger subjects. CONCLUSION: Our findings support the notion that AD-related neurodegenerative processes result from the concerted activity of multiple pathological mechanisms and factors that act inside and outside the brain and are dynamically affected by age and sex.

Hallucinations, somatic-functional disorders of PD-DLB as expressions of thalamic dysfunction.

Hallucinations, delusions, and functional neurological manifestations (conversion and somatic symptom disorders) of Parkinson's disease (PD) and dementia with Lewy bodies increase in frequency with disease progression, predict the onset of cognitive decline, and eventually blend with and are concealed by dementia. These symptoms share the absence of reality constraints and can be considered comparable elements of the PD-dementia with Lewy bodies psychosis. We propose that PD-dementia with Lewy bodies psychotic disorders depend on thalamic dysfunction promoting a theta burst mode and subsequent thalamocortical dysrhythmia with focal cortical coherence to theta electroencephalogram rhythms. This theta electroencephalogram activity, also called fast-theta or pre-alpha, has been shown to predict cognitive decline and fluctuations in Parkinson's disease with dementia and dementia with Lewy bodies. These electroencephalogram alterations are now considered a predictive marker for progression to dementia. The resulting thalamocortical dysrhythmia inhibits the frontal attentional network and favors the decoupling of the default mode network. As the default mode network is involved in integration of self-referential information into conscious perception, unconstrained default mode network activity, as revealed by recent imaging studies, leads to random formation of connections that link strong autobiographical correlates to trivial stimuli, thereby producing hallucinations, delusions, and functional neurological disorders. The thalamocortical dysrhythmia default mode network decoupling hypothesis provides the rationale for the design and testing of novel therapeutic pharmacological and nonpharmacological interventions in the context of PD, PD with dementia, and dementia with Lewy bodies. © 2019 International Parkinson and Movement Disorder Society.

Thalamic Involvement in Fluctuating Cognition in Dementia with Lewy Bodies: Magnetic Resonance Evidences.

Dementia with Lewy bodies (DLB) is characterized by fluctuation in cognition and attention. Thalamocortical connectivity and integrity of thalami are central to attentional function. We hypothesize that DLB patients with marked and frequent fluctuating cognition (flCog) have a loss of thalamocortical connectivity, an intrinsic disruption to thalamic structure and imbalances in thalamic neurotransmitter levels. To test this, magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and proton MR spectroscopy on thalami were performed on 16 DLB, 16 Alzheimer's disease (AD) and 13 healthy subjects. MRI and DTI were combined to subdivide thalami according to their cortical connectivity and to investigate microstructural changes in connectivity-defined thalamic regions. Compared with controls, lower N-acetyl-aspartate/total creatine (NAA/tCr) and higher total choline/total creatine (tCho/tCr) values were observed within thalami of DLB patients. tCho/tCr increase was found within right thalamus of DLB patients as compared with AD. This increase correlated with severity and frequency of flCog. As compared with controls, DLB patients showed bilateral damage within thalamic regions projecting to prefrontal and parieto-occipital cortices, whereas AD patients showed bilateral alteration within thalamic region projecting to temporal cortex. We posit that microstructural thalamic damage and cholinergic imbalance may be central to the etiology of flCog in DLB.