Altered Thalamo-Cortical White Matter Connectivity: Probabilistic Tractography Study in Clinical-High Risk for Psychosis and First-Episode Psychosis

Abstract

Disrupted thalamo-cortical connectivity is regarded as a core psychopathology in patients diagnosed with schizophrenia. However, whether the thalamo-cortical white matter connectivity is disrupted before the onset of psychosis is still unknown. To determine this gap in knowledge, the strength of thalamo-cortical white matter anatomical connectivity in subjects at clinical-high risk for psychosis (CHR) was compared to that of first-episode psychosis (FEP) and healthy controls. A total of 37 CHR, 21 FEP, and 37 matched healthy controls underwent diffusion-weighted magnetic resonance imaging to examine the number of probabilistic tractography "counts" representing thalamo-cortical white matter connectivity. We also investigated the relationship with psychopathology. For FEP, the connectivity between the thalamus and parietal cortex was significantly increased (F = 5.65, P < .05) compared to that of healthy controls. However, the connectivity between thalamus and orbitofrontal cortex was significantly reduced compared to both healthy controls (F = 11.86, P < .005) and CHR (F = 6.63, P < .05). Interestingly, CHR exhibited a similar pattern as FEP, albeit with slightly reduced magnitude. Compared to healthy controls, there was a significant decrease (F = 4.16, P < .05) in CHR thalamo-orbitofrontal connectivity. Also, the strength of the thalamo-orbitofrontal connectivity was correlated with the Global Assessment of Functioning score in CHR (r = .35, P < .05). This observed pattern of white matter connectivity disruptions in FEP and in CHR suggests that this pattern of disconnectivity not only highlights the involvement of thalamus but also might be useful as an early biomarker for psychosis.

Aberrant Temporal Connectivity in Persons at Clinical High Risk for Psychosis

“…Specifically, we expected an increase in functional connectivity between temporal areas and the thalamus consistent with previous findings in schizophrenia by Anticevic (26), showing increased thalamic connectivity with a set of lateral cortices (including the superior temporal gyrus) and with more recent findings of hyper- and hypoconnectivity of the thalamus with several cortical areas in individuals with psychotic illness (17). This hypothesis is also in line with reports of disrupted structural thalamo-cortical connectivity in CHR subjects and individuals with first episode psychosis (3). Moreover, recent evidence from animal models of schizophrenia points to a specific alteration of thalamic input to the auditory cortex subsequent to elevation in dopamine receptor levels in the thalamus (36) (37).…”

“…For each voxel, the MDMR analysis included: (1) Estimation of the whole-brain FC pattern of this voxel for each participant by calculating the Pearson’s correlation coefficient between the time series of this voxel and that of all other voxels within the group mask; (2) estimation of the spatial similarity (Pearson’s correlation) of the whole-brain connectivity pattern between pairs of participants; this yields an n × n correlation matrix, where n is the number of participants (n = 98 for categorical analysis and n = 51 for dimensional analyses); (3) conversion of each Pearson’s r into a distance measure using $\sqrt{2}\times \left(1-r\right)$ to produce an n × n distance matrix(41); (4) testing of the extent to which diagnostic status or symptom severity explains the distances of whole-brain connectivity between participants by using the following MDMR models(42): $$\begin{array}{c}left\text{Distance Matrix}=\mathrm{\beta }0+\mathrm{\beta }1\times \text{Group}+\mathrm{\beta }2\times \text{Age}+\mathrm{\beta }3\times \text{Sex}+\\ \mathrm{\beta }4\times \text{Handedness}+\mathrm{\beta }5\times \text{FD}\end{array}$$ $$\begin{array}{c}leftleft\text{Distance Matrix}=\mathrm{\beta }0+\mathrm{\beta }1\times \text{Total}\text{Positive}\text{Symptoms}\text{Score}+\mathrm{\beta }2\times \text{Age}+\mathrm{\beta }\\ left3\times \text{Sex}+\mathrm{\beta }4\times \text{Handedness}+\mathrm{\beta }5\times \text{FD}\end{array}$$…”

“…Schizophrenia is increasingly conceptualized as a brain disorder of abnormal anatomical (1–3) and functional connectivity(4–8). First, studies of functional connectivity have observed hyperconnectivity in the prefrontal cortex (9) and in the default mode network(10), though hypoconnectivity appears to be more frequently reported (4).…”

Family-based case-control study of homotopic connectivity in first-episode, drug-naive schizophrenia at rest

“…Second, predominantly positive and negative symptoms in the present patients may complicate the correlations between VMHC and clinical symptoms. For example, Cho et al 40. reported a significantly positive correlation between thalamo-orbitofrontal cortex connectivities and Global Assessment of Functioning scores in subjects with ultra-high risk for psychosis.…”

Thalamo-cortical communication, glutamatergic neurotransmission and neural oscillations: A unique window into the origins of ScZ?

“…However, more recent work has highlighted a more complex pattern of network abnormalities that involve both the reduction as well enhanced interactions that is captured by the concept of "dysconnectivty" (Stephan et al, 2009). Indeed, evidence is emerging for elevated connectivity mediated by TC-interactions in ScZ from several studies that have examined functional connectivity in early-stage ScZ with resting-state fMRI (Anticevic et al, 2015a;Cetin et al, 2014) and Diffusion Tensor Imaging (DTI) (Cho et al, 2015) (but see Woodword et al…”