The neurophysiological architecture of semantic dementia: spectral dynamic causal modelling of a neurodegenerative proteinopathy

Abstract

The selective destruction of large-scale brain networks by pathogenic protein spread is a ubiquitous theme in neurodegenerative disease. Characterising the circuit architecture of these diseases could illuminate both their pathophysiology and the computational architecture of the cognitive processes they target. However, this is challenging using standard neuroimaging techniques. Here we addressed this issue using a novel technique—spectral dynamic causal modelling—that estimates the effective connectivity between brain regions from resting-state fMRI data. We studied patients with semantic dementia—the paradigmatic disorder of the brain system mediating world knowledge—relative to healthy older individuals. We assessed how the effective connectivity of the semantic appraisal network targeted by this disease was modulated by pathogenic protein deposition and by two key phenotypic factors, semantic impairment and behavioural disinhibition. The presence of pathogenic protein in SD weakened the normal inhibitory self-coupling of network hubs in both antero-mesial temporal lobes, with development of an abnormal excitatory fronto-temporal projection in the left cerebral hemisphere. Semantic impairment and social disinhibition were linked to a similar but more extensive profile of abnormally attenuated inhibitory self-coupling within temporal lobe regions and excitatory projections between temporal and inferior frontal regions. Our findings demonstrate that population-level dynamic causal modelling can disclose a core pathophysiological feature of proteinopathic network architecture—attenuation of inhibitory connectivity—and the key elements of distributed neuronal processing that underwrite semantic memory.

The maternal brain is more flexible and responsive at rest: effective connectivity of the parental caregiving network in postpartum mothers

“…Importantly, as self-connections regulate the gain or excitability of superficial pyramidal cells within a region, they also regulate the precision of the prediction error. Thus, the finding that mothers show increased self-inhibition of the dorsomedial prefrontal cortex and parahippocampal gyrus is consistent with the interpretation that motherhood is associated with increased network efficiency (e.g., 60 ) and more precise prediction error 59,61 of the parental caregiving network relative to non-mothers. This improved precision for motherhood contrasts with pathologies like schizophrenia, which is associated with reduced self-connections and aberrant prediction error throughout the cortical hierarchy 59,61 .…”

“…Our findings suggest a selective modulation of inhibitory pathways in motherhood. Inhibition in a cortical hierarchy serves to maintain efficient neural signalling by modulation of the primary inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) 60,88 . In pregnancy and the postpartum period, GABAergic activation is modulated by fluctuating concentrations of neurosteroids, such as allopregnanolone (a metabolite of progesterone).…”

Processing of Degraded Speech in Brain Disorders

“…Although macroscopic neural network substrates that could support the required hierarchical and reciprocal information exchange have been delineated ( Figure 1 ), the predictive coding paradigm stipulates quite specifically how key elements such as “prediction generators” and “error detectors” are organised, both at the level of large-scale networks and local cortical circuits [ 14 , 235 ]. Neuroimaging techniques such as spectral dynamic causal modelling, MEG and high-field fMRI constitute particularly powerful and informative tools with which to interrogate the responsible neural elements and their interplay [ 14 , 236 ]: such techniques can capture both interactions between macroscopic brain modules and structure–function relationships at the level of individual cortical laminae, where the core circuit components of predictive coding are hypothesised to reside.…”

The problematic syndrome of right temporal lobe atrophy: Unweaving the phenotypic rainbow

“…These syndromes lie on a clinical and neuroanatomical continuum -their signatures increasingly converge with disease evolution (10)(11)(12)(13), and right temporal lobe involvement occurs early in even typical svPPA (14). In both syndromes, pathogenic protein spread targets a core, bitemporally distributed semantic appraisal network (10,(15)(16)(17). Furthermore, there is a strong, joint association with TAR-DNA-binding-protein (TDP)-43 type C as the underlying proteinopathy (3,6,11), albeit with greater genetic and histopathological heterogeneity in RTLA (18, 19).…”