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. 2009 Jan 20;106(3):912-7.
doi: 10.1073/pnas.0807041106. Epub 2009 Jan 12.

Psychosocial stress reversibly disrupts prefrontal processing and attentional control

C Liston  1 , B S McEwen, B J Casey
Affiliations

Psychosocial stress reversibly disrupts prefrontal processing and attentional control

C Liston et al. Proc Natl Acad Sci U S A. .

Abstract

Relatively little is known about the long-term neurobiological sequelae of chronic stress, which predisposes susceptible patients to neuropsychiatric conditions affecting the prefrontal cortex (PFC). Animal models and human neuroimaging experiments provide complementary insights, yet efforts to integrate the two are often complicated by limitations inherent in drawing comparisons between unrelated studies with disparate designs. Translating from a rodent model of chronic stress where we have shown reversible disruption of PFC function, we show that psychosocial stress induces long-lasting but reversible impairments in behavioral and functional magnetic resonance imaging (fMRI) measures of PFC function in humans. Twenty healthy adults, exposed to 1 month of psychosocial stress, confirmed by a validated rating scale, were scanned while performing a PFC-dependent attention-shifting task. One month later, they returned for a second scanning session after a period of reduced stress, and their performance was compared with a twice-scanned, matched group of low-stress controls. Psychosocial stress selectively impaired attentional control and disrupted functional connectivity within a frontoparietal network that mediates attention shifts. These effects were reversible: after one month of reduced stress, the same subjects showed no significant differences from controls. These results highlight the plasticity of PFC networks in healthy human subjects and suggest one mechanism by which disrupted plasticity may contribute to cognitive impairments characteristic of stress-related neuropsychiatric conditions in susceptible individuals.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Chronic psychosocial stress selectively impaired attention shifting. (A) Attention-shift paradigm. Subjects viewed two moving, circular square-wave gratings on each trial and were cued to respond on the basis of either the color (“C”) or the motion (“M”) of the stimuli. Attention shifting was assessed by contrasting shift trials—defined as those preceded by 2–5 trials of the opposite dimension—with repeat trials, which were preceded by 2–5 trials of the same dimension but were otherwise identical. (B) Reversal learning paradigm. On some shift trials (“reversals”), the target response for the color dimension (red) was paired with the nontarget for the motion dimension (down), so the subject was required to override the response learned in the previous block of repeats. On others, the target response was the same in both dimensions. Response reversals were assessed by contrasting shift trials that required a reversal of the prepotent response learned in the previous block of repeats with those that did not. (C) Psychosocial stress impaired attention shifts. Across subjects, PSS scores predicted larger attention shift costs (r = 0.51, P = 0.002). (D) Stress effects on attention shifts were specific: PSS scores were not associated with reversal costs (r = 0.10, P = 0.56).
Fig. 2.
Fig. 2.
Flexible attentional control depends on the integrity of a frontoparietal network that includes DLPFC. (A) Attention shifts engaged DLPFC bilaterally (P < 0.05, corrected). (B) The areas depicted in A served as seed volumes for a functional connectivity analysis that quantified coupling between DLPFC and other areas of a frontoparietal network that was active during attention shifts, including anterior cingulate (ACC), ventrolateral prefrontal (VLPFC), insula, premotor, ventral and dorsal areas of the posterior parietal cortex (PPC), and occipitotemporal visual areas including the fusiform cortex (P < 0.05, corrected). (C) Attention-shift performance depended on the integrity of this network. Decreased functional connectivity between left (i) and right (ii) DLPFC and areas of posterior parietal and premotor cortex was correlated with impaired attention shifting, independent of stress effects (P < 0.05, corrected). Scatterplots depict results for peak voxels in each cluster. See SI for details. ***, P < 0.005.
Fig. 3.
Fig. 3.
Chronic stress reversibly disrupted DLPFC functional connectivity. (A) Psychosocial stress exposure in the month preceding the first scanning session was associated with altered functional connectivity in left and right DLPFC. (Left) Stress decreased coupling between left DLPFC and right DLPFC, premotor, ventral PFC (insula), and posterior parietal cortex (PPC) relative to controls. Stress increased coupling with middle temporal lobe areas. (Right) Psychosocial stress decreased coupling between right DLPFC and left DLPFC, anterior cingulate (ACC), premotor, ventral PFC (insula), putamen, ventral PPC, posterior cingulate (PCC), fusiform cortex, and cerebellum. Maps represent post hoc t-tests of the stress effect. (B) Stress-exposed subjects were retested after 1 month of reduced stress and showed no differences from control subjects on PSS scores (i: t = 0.88, P = 0.39) or attention-shift costs (ii: t = 0.05, P = 0.96). (C) Stress effects on left (i) and right (ii) DLPFC functional connectivity reversed after 1 month of reduced stress for all areas tested except ventrolateral PFC. This reversal was confirmed by a significant stress-by-session interaction for all areas within a search volume that included voxels showing a significant main effect of stress overall. Other areas showed a comparable trend: stressed subjects showed altered connectivity in session 1 (red bars) but not in session 2 (blue bars). Data are plotted relative to mean values in low-stress control subjects. Error bars, SEM; NS, not significant; †, interaction significant at P < 0.05; t-tests, *, P < 0.05; **, P < 0.01; ***, P < 0.005.
Fig. 4.
Fig. 4.
Stress effects on human PFC function (Bottom) are consistent with those observed in a rodent model of chronic stress (Top). Data from the rodent model are reproduced with permission from ref. (Copyright 2006, The Journal of Neuroscience). (A) Chronic stress disrupted DLPFC functional connectivity in human subjects (t = 5.74, P < 0.001) and reduces apical dendritic arborization in rats (t = 2.83, P = 0.007). Human functional connectivity values represent the group means for peak voxels in each of the affected regions depicted in Fig. 3 A and C. (B) Stress-induced corresponding impairments in attention shifting [humans (Bottom), t = 2.10, P = 0.04; rats (Top), t = 3.51, P = 0.002). (C) Measures of PFC integrity predicted attention-shifting impairments in humans (Bottom) (r = −0.64, P < 0.001) and showed a similar trend in rats (Top) (r = −0.74, P = 0.09). Human functional connectivity values represent the means for peak voxels in each of the 6 regions depicted in the scatterplots in Fig. 2C. Error bars, SEM; *, P < 0.05; **, P < 0.01; ***, P < 0.005.
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