Activation of brainstem and midbrain nuclei during cognitive control in medicated patients with schizophrenia

Abstract

Evidence suggests that cognitive control functions as well as the underlying brain network, anchored by the prefrontal cortex (PFC) and the dorsal anterior cingulate cortex (dACC), are dysfunctional in schizophrenia. Catecholamine producing midbrain and brainstem nuclei are densely connected with the PFC and dACC and exert profound contributions to cognitive control processes. Dysfunctions within the underlying neurotransmitter systems are considered to play a central role in the occurrence of various symptoms of schizophrenia. We sought to investigate the putatively abnormal activation pattern of the dopaminergic midbrain nuclei, that is, ventral tegmental area (VTA) and substantia nigra as well as that of the noradrenergic locus coeruleus (LC) in patients with schizophrenia during cognitive control. A total of 28 medicated patients and 27 healthy controls were investigated with the manual version of the Stroop task using event-related fMRI. The main finding was a reduced BOLD activation in the VTA during both Stroop task conditions in patients in comparison to controls, which correlated significantly with the degree of negative symptoms. We further detected a comparable LC activation in in patients and healthy controls. However, in controls LC activation was significantly correlated with the Stroop interference time, which was not observed in patients. The finding of reduced VTA activation in schizophrenia patients lends further support to the assumed dysfunction of the DA system in schizophrenia. In addition, despite comparable LC activation, the nonsignificant correlation with the Stroop interference time might indicate altered LC functioning in schizophrenia and, thus, needs further investigations.

Real-world stress resilience is associated with the responsivity of the locus coeruleus

“…These data are consistent with the hypothesis that pupil-linked arousal mechanisms regulate conflict adjustments in nonhuman primates 60,61 . Moreover, several prior human functional imaging reports show reliable involvement of LC-NE system during conflict resolution involving stroop-tasks [62][63][64] as well as during tasks requiring the resolution of unexpected uncertainty 65 . We chose the conflict task over another standard task reported to activate the arousal system, the odd-ball task 66 , because a previous report indicated no correlation between human LC-odd-ball-responses and any additional physiological measure such as pupil-dilation, skin-conductance or heartrate 46 .…”

The role of norepinephrine in the pathophysiology of schizophrenia

“…An increasing number of studies focused on the NE system in SCZ, in particular by combining two or more of the available methods (Table 4), will give us a more complete picture of the disease. Some recent work has been done in this direction (Köhler et al, 2019;Minzenberg et al, 2018). A starting point could be to directly evaluate the triple-networks model (Fig.…”

Functional connectome of brainstem nuclei involved in autonomic, limbic, pain and sensory processing in living humans from 7 Tesla resting state fMRI

“…The copyright holder for this preprint this version posted October 19, 2021. ; https://doi.org/10.1101/2021.10.18.464861 doi: bioRxiv preprint 6 et al, 2017], psychiatric diseases [Köhler et al, 2019;Mochcovitch et al, 2014;Syan et al, 2018], and vestibular disorders [Roberts et al, 2018] .…”

“…Further, we inspected the feasibility/limitations of mapping a similar brainstem connectome using conventional 3 Tesla data. Translatability to clinical studies is important to enable the investigation of pathological conditions involving autonomic, limbic, nociceptive and sensory functions, such as autonomic impairments [Henderson et al, 2006;Khazaie et al, 2017], psychiatric diseases [Köhler et al, 2019;Mochcovitch et al, 2014;Syan et al, 2018], and vestibular disorders [Roberts et al, 2018] .…”