Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia

Abstract

Importance Despite the well-established role of striatal dopamine in psychosis, current views generally agree that cortical dysfunction is likely necessary for the emergence of psychotic symptoms. The topographical organization of striatal-cortical connections is central to gating and integration of higher-order information, so a disruption of such topography via dysregulated dopamine could lead to cortical dysfunction in schizophrenia. However, this hypothesis remains to be tested using multivariate methods ascertaining the global pattern of striatal connectivity and without the confounding effects of anti-dopaminergic medication. Objective To determine whether the pattern of brain connectivity across striatal subregions is abnormal in unmedicated patients with schizophrenia, and whether this abnormality relates to psychotic symptoms and extrastriatal dopaminergic transmission. Design and Participants In this multimodal, case-control study, we obtained resting-state functional Magnetic Resonance Imaging (fMRI) data in 18 unmedicated patients with schizophrenia and 24 matched healthy controls. A subset of these (12 and 17, respectively) underwent Positron Emission Tomographic (PET) imaging with the dopamine D2-receptor radiotracer [11C]FLB457, before and after amphetamine. Data were acquired between June 16, 2011, and February 25, 2014. Main Outcomes (1) Group differences in the striatal connectivity pattern (assessed via multivariable logistic regression) across striatal subregions, and the relationship between the multivariate striatal connectivity pattern (2) with extrastriatal baseline D2-receptor binding potential and its change following amphetamine (BPND and ΔBPND), and (3) with severity of positive symptoms evaluated with the PANSS scale. Results Patients exhibited an abnormal pattern of striatal connectivity, which included abnormal caudate connections with a distributed set of associative cortex regions (p=0.0036). In patients, more deviation from the multivariate pattern of striatal connectivity found in controls correlated specifically with more severe positive symptoms (p=0.0021). Striatal connectivity also correlated with baseline BPND across cortical and extrastriatal subcortical regions (p=0.0116, Bonferroni-corrected) but not with ΔBPND. Conclusions and Relevance Using a multimodal, circuit-level interrogation of striatal-cortical connections, we provide a first demonstration that the functional topography of these connections is globally disrupted in unmedicated patients with schizophrenia. These findings suggest that striatal-cortical dysconnectivity may underlie the effects of dopamine dysregulation on the pathophysiology of psychotic symptoms.

Psychosis risk is associated with decreased resting-state functional connectivity between the striatum and the default mode network

“…Overall, in the present study we found novel evidence of decreased resting-state functional connectivity between the striatum and the cortical default mode network in psychosis risk. This adds to other research implicating the dorsal caudate as a region where decreased connectivity to cortical regions is associated with psychosis (e.g., Horga et al, 2016). The present findings also appear to be generally consistent with the aberrant-salience view of psychosis (Kapur, 2003), and with evidence of self-relevance processing disturbances in psychosis risk and psychotic disorders (Nelson et al, 2009).…”

Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases

“…In this perspective, early-onset alterations of experience-dependent plasticity would interfere with structural and functional connectivity subserving the acquisition of basic neurological and socio-cognitive skills in DS Galderisi et al, 2008;Peralta et al, 2014;Wheeler et al, 2015). The onset of psychosis might add to this altered connectivity producing a further impairment in brain plasticity related to abnormal salience attribution to stimuli and events with no intrinsic reward value (Horga et al, 2016;Howes and Kapur, 2009). If PNS and DS are the results of pervasive neurodevelopmental disorders, the implication for treatment are complex: a combination of psychosocial rehabilitation programs and techniques to improve brain plasticity should be implemented to favor the development of never-acquired functions and facilitate experience-dependent plastic changes to re-shape functional and structural connectivity within relevant networks.…”

Functional dysconnectivity of the limbic loop of frontostriatal circuits in first‐episode, treatment‐naive schizophrenia

“…ume, reduced fractional anisotropy(Levitt et al, 2017;Quide, Morris, Shepherd, Rowland, & Green, 2013), increased synaptic dopamine function(Horga et al, 2016;Meyer-Lindenberg et al, 2002), increased glutamate levels (de la Fuente-Sandoval et al, 2013), and lower activations or connectivity(Mucci et al, 2015;Peters et al, 2017;Zhou et al, 2007), most of those previous studies recruited chronic patients, or the early-stage SZ patients who had already received the antipsychotic medications. Therefore, the current finding of lacking the associative loop impairment in medication-naïve FESZ suggested that associative loop and their related cognitive function may be progressively present with the development of disease and mainly in the field of active consciousness.…”