Medial prefrontal cortex damage affects physiological and psychological stress responses differently in men and women
Introduction
A wealth of research has focused on understanding the neural regulation of the stress response (McEwen, 2000, Herman et al., 2003, Lovallo, 2005). This work has highlighted the importance of the hypothalamus and pituitary gland as key controllers of stress reactivity, but many forebrain areas such as the medial prefrontal cortex (mPFC; Diorio et al., 1993, Sullivan and Gratton, 1999, Maier et al., 2006), amygdala (Feldman et al., 1995, Jankord and Herman, 2008) and hippocampus (HC; Sapolsky et al., 1984, Herman et al., 2003) are also involved. The role that these structures play in determining the stress-inducing nature of a stimulus and enacting a stress response has been addressed mostly with animal models. More recent work has focused on these issues in humans, using either the lesion method (Buchanan et al., 2004, Buchanan et al., 2009, Wolf et al., 2005) or functional neuroimaging (Wang et al., 2005, Urry et al., 2006, Kern et al., 2008, Pruessner et al., 2008). This work has generally provided evidence supporting the roles of the mPFC, hippocampus, and amygdala in controlling the stress response in humans.
The mPFC is involved in the control of many aspects of stress and emotion. Humans with bilateral damage to this region show deficits in the regulation of emotion in laboratory tasks as well as in their daily lives (Bechara et al., 1994, Anderson et al., 2006). The pattern of disturbed emotion regulation in these individuals (sometimes termed ‘frontal disinhibition syndrome’) includes flattened affect as well as impulsivity, risk taking, and emotional outbursts that are incommensurate with the provocation (Barrash et al., 2000, Berlin et al., 2004, Floden et al., 2008). Although electrodermal responses after mPFC damage tend to be reduced in response to emotional stimuli (Tranel and Damasio, 1994), some studies have reported pronounced cardiovascular activation in mPFC lesion patients (Critchley et al., 2003, Hilz et al., 2006). Critchley et al. (2003) demonstrated increased heart rate and decreased heart rate variability to mental stress in patients with mPFC (specifically anterior cingulate) damage, suggesting reduced inhibitory control of the heart after mPFC damage. Further, neuroimaging studies have suggested that the mPFC exerts inhibitory control over autonomic and endocrine output (Wang et al., 2005, Ahs et al., 2006, Urry et al., 2006, Kern et al., 2008, Pruessner et al., 2008, Lane et al., 2009). Damage to this region, then, could result in a disinhibition of psychological and physiological responses to stress.
The mPFC is not a unitary structure; many studies have documented different functions for the left versus right mPFC and of the ventral versus dorsal regions. Rats with lesions to the right mPFC show decreased stress reactivity, while left-sided damage does not affect the stress response (Sullivan and Gratton, 1999). In work with humans, Tranel et al. (2002) have shown that patients with damage to the right ventral mPFC show a pattern of disturbed social and emotional behavior akin to that previously described for patients with bilateral damage to this region, whereas patients with left-sided damage do not show this pattern. More recent work suggests that this asymmetric pattern of disturbance following unilateral lesions is different between the sexes, such that men with right-sided, but not left-sided damage and women with left-sided, but not right-sided damage show this altered social and emotional behavior, following damage to the mPFC (Tranel et al., 2005) or the amygdala (Tranel and Bechara, 2009). A large body of research has documented sex differences in a host of neural functions (see Cahill, 2005). This work has documented sex differences in neural activity during cognitive tasks such as memory (Andreano and Cahill, 2009) and naming (Grabowski et al., 2003) as well as in more “emotional” tasks such as memory for emotion (Buchanan and Tranel, 2008) and in the cognitive control of emotional processing (Koch et al., 2007, McRae et al., 2008). These findings suggest that reactions to stress may depend on different neural structures for men and women.
Psychological stress is unique in that the stressful nature of the situation is determined by its perceived threat value, which may be unrelated to the actual threat of a situation (Lazarus and Folkman, 1984). For example, some people may perceive the act of giving a speech to be terrifying, while others may perceive the act to be a neutral, or even a positive situation. This model of stress proposes that the interaction between the stressor and an individual's appraisal processes result in the stress response. These appraisals are processed by neural areas including the mPFC (Rudebeck et al., 2008), which in turn activate hypothalamic and brain stem regions responsible for the initiation of the physiological stress response (Öngür et al., 1998).
Patients with mPFC damage have difficulty interpreting social and emotional cues (Hornak et al., 1996, Beer et al., 2003, Mah et al., 2004, Heberlein et al., 2008). Damage to the mPFC may therefore impair the appreciation of the stressful nature of a situation, leading to inappropriate psychological and physiological reactivity to social stress, which could be manifested through either hypo- or hyper-reactivity. A number of investigators have noted this frontal disinhibition pattern in individuals with damage to the mPFC. Jarvie (1954) gave several examples of disinhibitory behavior in such patients. One of these patients, who had bilateral damage to the frontal poles, described, in a flat, matter-of-fact manner “… how the girl whom he had intended marrying had become pregnant by another man…” In spite of this blunted affect when describing a presumably emotional event, in his daily life the patient “… admitted to being very irritable at times, losing his temper, and on occasions smashing some articles at home.” The patient's volatility was corroborated by his mother, who described him as “… bad-tempered, irritable, and frightening in his aggressiveness.” (see also Koenigs and Tranel, 2007 for other examples of such a discrepancy between baseline blunted affect coupled with emotional outbursts).
Psychological stress may present a real challenge for individuals with mPFC damage because the stressful nature of a situation depends on one's appraisal of the situation. If these individuals have difficulty interpreting the stressful nature of a situation that others may describe as stressful, they may produce an abnormal response to the situation. This study had three objectives: The first objective was to examine the stress responses of participants with mPFC lesions. To do this, we measured salivary cortisol, heart rate, heart rate variability, and subjective affective responses to an orthostatic challenge and the Trier Social Stress Test (TSST). The orthostatic challenge was designed to assess basic autonomic function and the Trier Social Stress Test (TSST) to assess reactivity to psychological stress. We anticipated that, given the pattern of disinhibition shown by mPFC lesion patients, they would show abnormal reactivity to stress compared to comparison groups. Given the altered emotional regulation pattern shown by these patients, we were agnostic about the direction of their response to stress. The second objective was to address whether the laterality of mPFC lesions was associated with stress reactivity. To address this issue, we compared stress reactivity between those with left- and right-sided damage and we examined the extent of damage to the right versus left mPFC in each participant using analysis of lesion volumes of the mPFC from magnetic resonance imaging (MRI) or computed tomography (CT). Based on prior work, we predicted that right-sided damage would be associated with greater stress reactivity. The third objective was to examine the role that sex may play in the relationship between the mPFC and stress. These analyses were exploratory in nature given the small sample size to detect both sex and laterality effects.
Section snippets
Participants
Eighteen participants with brain damage including the mPFC (see Fig. 1 for lesion overlap), 12 participants with brain damage outside the PFC, and 54 healthy volunteers participated in the study (see Table 1 for participant characteristics). Causes of damage in the mPFC group were: seven with meningioma resections, five with subarachnoid hemorrhage after anterior communicating artery aneurysm rupture, two with frontal infarctions, two with trauma, one subarachnoid cyst removal, and one
Results
The basic findings of the study indicate that damage to the mPFC does alter subjective, hormonal, and autonomic stress reactivity (addressing objective 1 outlined in Section 1). Further, laterality of lesion does not seem to influence this reactivity (ala objective 2). Finally, these effects are different between men and women (ala objective 3). Specific results are outlined below with reference to the overall objectives.
Discussion
The ability to recognize a situation as stressful and produce the appropriate psychological and physiological responses is necessary for adaptive behavior. Both over reactions and under reactions could lead to inappropriate psychological and physiological responses to stress. Results from this study show that damage to a region of the brain known to be necessary for the proper regulation of emotional reactivity leads to a disinhibited pattern of stress reactivity. Specifically, patients with
Conflict of interest
None declared.
Acknowledgements
We would like to thank Joel Bruss and Dr. Thomas Grabowski of the Laboratory for Computational Neuroimaging, Department of Neurology, University of Iowa for sharing their expertise and resources. This study was funded by a NIMH grantR03 076815 and a NARSAD Young Investigator awarded to TWB, and NIDA grantR01 022549 awarded to DT, and NINDS grantP01 19632 awarded to DT.
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