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Cited by 43Hallucinations in medical conditionsPsychedelics and Drug StudiesFunctional Brain Connectivity Studies

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

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Onofrj, Marco, Russo, Mirella, Delli Pizzi, Stefano, De Gregorio, Danilo, Inserra, Antonio, Gobbi, Gabriella, Sensi, Stefano L.·2023·Translational Psychiatry
DOI 10.1038/s41398-023-02691-0PMC PMC10719401
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Abstract

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.

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Fig. 1 Network changes occurring upon the PD-DLB psychosis complex and psychedelics. A Upon physiological conditions, the cholinergic transmission from the pedunculopontine nuclei inhibits the thalamic reticular nuclei, activates the high-order thalamic nuclei, and produces high-frequency cortical oscillations (tonic mode). These activities suppress DMN functioning and increase TPN engagement. B Upon unconsciousness or during REM sleep, the down-regulation of cholinergic projections from the pedunculopontine nuclei to the thalamic reticular nuclei deactivates the high-order thalamic nuclei, promotes low-frequency oscillations (burst-firing mode), and decreases the thalamic control exerted on the DMN. C, D Pathological pedunculopontine nuclei changes in PD/DLB patients or psychedelic-driven 5-HT modulation disinhibits the thalamic reticular nuclei. The overactivated thalamic reticular nuclei inhibit the high-order thalamic nuclei and produce low-frequency oscillations (burst-firing mode), thereby uncoupling the DMN by decreasing the thalamic control of the network. The red and blue colors indicate down- or up-regulation of the brain systems, respectively. DLB, Dementia with Lewy Bodies, DMN Default Mode Network, MD mediodorsal nuclei, PD Parkinson’s Disease, PN posterior nuclei, PPN peduncolopontine nuclei, TPNs task-positive networks, TRN thalamic reticular nuclei.
Fig. 1 Network changes occurring upon the PD-DLB psychosis complex and psychedelics. A Upon physiological conditions, the cholinergic transmission from the pedunculopontine nuclei inhibits the thalamic reticular nuclei, activates the high-order thalamic nuclei, and produces high-frequency cortical oscillations (tonic mode). These activities suppress DMN functioning and increase TPN engagement. B Upon unconsciousness or during REM sleep, the down-regulation of cholinergic projections from the pedunculopontine nuclei to the thalamic reticular nuclei deactivates the high-order thalamic nuclei, promotes low-frequency oscillations (burst-firing mode), and decreases the thalamic control exerted on the DMN. C, D Pathological pedunculopontine nuclei changes in PD/DLB patients or psychedelic-driven 5-HT modulation disinhibits the thalamic reticular nuclei. The overactivated thalamic reticular nuclei inhibit the high-order thalamic nuclei and produce low-frequency oscillations (burst-firing mode), thereby uncoupling the DMN by decreasing the thalamic control of the network. The red and blue colors indicate down- or up-regulation of the brain systems, respectively. DLB, Dementia with Lewy Bodies, DMN Default Mode Network, MD mediodorsal nuclei, PD Parkinson’s Disease, PN posterior nuclei, PPN peduncolopontine nuclei, TPNs task-positive networks, TRN thalamic reticular nuclei.CC BY · PubMed Central
Fig. 2 Model for psychosis upon PD-DLB or psychedelics. Left panel: Upon physiological conditions, the prefrontal cortex modulates the activity of the ventral striatum and temporal structures like the amygdala and parahippocampus, thereby filtering correct responses to incoming somatosensory stimuli. For instance, the amygdala shapes the integration of body perceptions and cognitive-affective information upon sensory processing. The ventral striatum modulates thalamic filtering of first-order nuclei and the physiological flux of information that, via direct connections or indirectly, via the insula, gain access to the somatosensory cortex. The thalamic high-order nuclei are relevant to shape cortico-cortical interactions, particularly connections within the DMN or between the DMN and TPN. Right panel Upon psychotic conditions associated with PD-DLB or triggered by psychedelics, the deregulation of the prefrontal cortex generates aberrant activity within the ventral striatum and the abovementioned temporal structures. The result is the production of out-of-control responses to incoming somatosensory stimuli and imbalanced integration of body perceptions and cognitive-affective information that occurs upon sensory processing. The dysfunctional activity of the ventral striatum decreases the thalamic filtering of first-order nuclei. It favors the production of an abnormal flux of information to the sensory cortices and triggers enhanced responses to peripheral stimuli and enhanced sensory coding of stimuli. The activation of 5-HT2A receptors by psychedelics or cholinergic imbalance along the thalamo-PPN pathway promotes thalamo-cortical dysrhythmia, which increases the overactivation of the PCC. This cascade of events induces postero-frontal disconnections within the DMN, reinforces frontal dysfunction, and decouples the DMN from TPN. The red and blue colors indicate down- or up-regulation of the brain systems, respectively. DLB Dementia with Lewy Bodies, mPFC ventro-medial prefrontal cortex, PCC posterior cingulate cortex, PD Parkinson’s Disease, SE sensorimotor cortex, THAL thalamus, VS ventral striatum, Temp temporal structure, VIS visual cortex.
Fig. 2 Model for psychosis upon PD-DLB or psychedelics. Left panel: Upon physiological conditions, the prefrontal cortex modulates the activity of the ventral striatum and temporal structures like the amygdala and parahippocampus, thereby filtering correct responses to incoming somatosensory stimuli. For instance, the amygdala shapes the integration of body perceptions and cognitive-affective information upon sensory processing. The ventral striatum modulates thalamic filtering of first-order nuclei and the physiological flux of information that, via direct connections or indirectly, via the insula, gain access to the somatosensory cortex. The thalamic high-order nuclei are relevant to shape cortico-cortical interactions, particularly connections within the DMN or between the DMN and TPN. Right panel Upon psychotic conditions associated with PD-DLB or triggered by psychedelics, the deregulation of the prefrontal cortex generates aberrant activity within the ventral striatum and the abovementioned temporal structures. The result is the production of out-of-control responses to incoming somatosensory stimuli and imbalanced integration of body perceptions and cognitive-affective information that occurs upon sensory processing. The dysfunctional activity of the ventral striatum decreases the thalamic filtering of first-order nuclei. It favors the production of an abnormal flux of information to the sensory cortices and triggers enhanced responses to peripheral stimuli and enhanced sensory coding of stimuli. The activation of 5-HT2A receptors by psychedelics or cholinergic imbalance along the thalamo-PPN pathway promotes thalamo-cortical dysrhythmia, which increases the overactivation of the PCC. This cascade of events induces postero-frontal disconnections within the DMN, reinforces frontal dysfunction, and decouples the DMN from TPN. The red and blue colors indicate down- or up-regulation of the brain systems, respectively. DLB Dementia with Lewy Bodies, mPFC ventro-medial prefrontal cortex, PCC posterior cingulate cortex, PD Parkinson’s Disease, SE sensorimotor cortex, THAL thalamus, VS ventral striatum, Temp temporal structure, VIS visual cortex.CC BY · PubMed Central
Fig. 3 Decreased thalamic filtering in Parkinson’s disease-DLB. A The scheme depicts the cortico-striato-thalamo-cortical loop that physiologically controls the gating activity exerted by the first-order thalamic nuclei (ventral posterior and lateral geniculate nuclei) on external inputs. Upon physiological conditions, the cortico-striato-thalamo-cortical activity is positively modulated by glutamatergic projections that descend from the prefrontal cortex and are inhibited by the mesolimbic dopaminergic or serotoninergic projections originating from the midbrain. B The dysfunctional activity of the cortico-striato-thalamo-cortical loop results in decreased filtering operated by the first-order thalamic nuclei and generates a sensory overflow to the primary cortices. The mechanism works synergistically with the TCD (see also Fig. 2, panels C, D) and contributes to the increased engagement of the DMN. The red and blue colors indicate down- or up-regulation of the brain systems, respectively. CSTC cortico-striato-thalamo-cortical loop, DLB Dementia with Lewy Bodies, DMN Default Mode Network, Glu glutamate, LGN lateral geniculate nucleus, PD Parkinson’s Disease, PFC prefrontal cortex, TCD Thalamocortical Dysrhythmia, VPN ventral posterior nucleus.
Fig. 3 Decreased thalamic filtering in Parkinson’s disease-DLB. A The scheme depicts the cortico-striato-thalamo-cortical loop that physiologically controls the gating activity exerted by the first-order thalamic nuclei (ventral posterior and lateral geniculate nuclei) on external inputs. Upon physiological conditions, the cortico-striato-thalamo-cortical activity is positively modulated by glutamatergic projections that descend from the prefrontal cortex and are inhibited by the mesolimbic dopaminergic or serotoninergic projections originating from the midbrain. B The dysfunctional activity of the cortico-striato-thalamo-cortical loop results in decreased filtering operated by the first-order thalamic nuclei and generates a sensory overflow to the primary cortices. The mechanism works synergistically with the TCD (see also Fig. 2, panels C, D) and contributes to the increased engagement of the DMN. The red and blue colors indicate down- or up-regulation of the brain systems, respectively. CSTC cortico-striato-thalamo-cortical loop, DLB Dementia with Lewy Bodies, DMN Default Mode Network, Glu glutamate, LGN lateral geniculate nucleus, PD Parkinson’s Disease, PFC prefrontal cortex, TCD Thalamocortical Dysrhythmia, VPN ventral posterior nucleus.CC BY · PubMed Central

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Metadata

Authors
Onofrj, M., Russo, M., Delli Pizzi, S., De Gregorio, D., Inserra, A., Gobbi, G., & Sensi, S. L.
Affiliations
  • University of Chieti-Pescara (IT)
  • McGill University (CA)
Corresponding author
  • Onofrj, Marco
  • Sensi, Stefano L.
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2023-12-13
Volume
13
Issue
1
Pages
384-384
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-023-02691-0
PMC
PMC10719401
OpenAlex
W4389684661
Cited by
43
References
233
Citations by year
2026: 18 · 2025: 14 · 2024: 11
FWCI
1.62
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Alzheimer's Association (18PTC-19-602325, 18PTC-19-602325 and GEENA-Q-19-596282, GEENA-Q-19-596282, 602325)
  • European Commission (HORIZON2020)
  • Associazione Italiana Ricerca Alzheimer (18PTC-19-602325, GEENA-Q-19-596282)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Hallucinations in medical conditions
  • Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Functional Brain Connectivity Studies
Keywords
thalamus, psychosis, Parkinson's disease, dementia with Lewy bodies, hallucinations, delusions, somatic symptom disorder, thalamocortical dysrhythmia, default mode network, altered states of consciousness, psychedelics, thalamocortical circuits, neurodegenerative diseases
MeSH terms
Hallucinogens, Humans, Parkinson Disease, Psychotic Disorders, Thalamus, Neurodegenerative Diseases, Lewy Body Disease

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