Carissa L. Philippi

Damage to Association Fiber Tracts Impairs Recognition of the Facial Expression of Emotion

An array of cortical and subcortical structures have been implicated in the recognition of emotion from facial expressions. It remains unknown how these regions communicate as parts of a system to achieve recognition, but white matter tracts are likely critical to this process. We hypothesized that (1) damage to white matter tracts would be associated with recognition impairment and (2) the degree of disconnection of association fiber tracts [inferior longitudinal fasciculus (ILF) and/or inferior fronto-occipital fasciculus (IFOF)] connecting the visual cortex with emotion-related regions would negatively correlate with recognition performance. One hundred three patients with focal, stable brain lesions mapped onto a reference brain were tested on their recognition of six basic emotional facial expressions. Association fiber tracts from a probabilistic atlas were coregistered to the reference brain. Parameters estimating disconnection were entered in a general linear model to predict emotion recognition impairments, accounting for lesion size and cortical damage. Damage associated with the right IFOF significantly predicted an overall facial emotion recognition impairment and specific impairments for sadness, anger, and fear. One subject had a pure white matter lesion in the location of the right IFOF and ILF. He presented specific, unequivocal emotion recognition impairments. Additional analysis suggested that impairment in fear recognition can result from damage to the IFOF and not the amygdala. Our findings demonstrate the key role of white matter association tracts in the recognition of the facial expression of emotion and identify specific tracts that may be most critical.

Ventromedial Prefrontal Cortex Is Critical for the Regulation of Amygdala Activity in Humans

BACKGROUND Dysfunction in the ventromedial prefrontal cortex (vmPFC) is believed to play a pivotal role in the pathogenesis of mood and anxiety disorders. Leading neurocircuitry models of these disorders propose that hypoactivity in the vmPFC engenders disinhibited activity of the amygdala and, consequently, pathologically elevated levels of negative affect. This model predicts that a selective loss or diminution of function of the vmPFC would result in heightened activity of the amygdala. Although this prediction has been borne out in rodent lesion and electrophysiologic studies using fear conditioning and extinction paradigms, there has not yet been a definitive test of this prediction in humans. METHODS We tested this prediction through a novel use of functional magnetic resonance imaging in four neurosurgical patients with focal, bilateral vmPFC damage. RESULTS Relative to neurologically healthy comparison subjects, the patients with vmPFC lesions exhibited potentiated amygdala responses to aversive images and elevated resting-state amygdala functional connectivity. No comparable group differences were observed for activity in other brain regions. CONCLUSIONS These results provide unique evidence for the critical role of the vmPFC in regulating activity of the amygdala in humans and help elucidate the causal neural interactions that underlie mental illness.

Cortical Thinning in Psychopathy

OBJECTIVE Psychopathy is a personality disorder associated with severely antisocial behavior and a host of cognitive and affective deficits. The neuropathological basis of the disorder has not been clearly established. Cortical thickness is a sensitive measure of brain structure that has been used to identify neurobiological abnormalities in a number of psychiatric disorders. The authors assessed cortical thickness and corresponding functional connectivity in psychopathic prison inmates. METHOD Using T1 MRI data, the authors computed cortical thickness maps in a sample of adult male prison inmates selected on the basis of psychopathy diagnosis (21 psychopathic inmates and 31 nonpsychopathic inmates). Using restingstate functional MRI data from a subset of these inmates (20 psychopathic inmates and 20 nonpsychopathic inmates), the authors then computed functional connectivity within networks exhibiting significant thinning among psychopaths. RESULTS Relative to nonpsychopaths, psychopaths had significantly thinner cortex in a number of regions, including the left insula and dorsal anterior cingulate cortex, the left and right precentral gyri, the left and right anterior temporal cortices, and the right inferior frontal gyrus. These neurostructural differences were not due to differences in age, IQ, or substance use. Psychopaths also exhibited a corresponding reduction in functional connectivity between the left insula and the left dorsal anterior cingulate cortex. CONCLUSIONS Psychopathy is associated with a distinct pattern of cortical thinning and reduced functional connectivity.

Medial pfc damage abolishes the self-reference effect

Functional neuroimaging studies suggest that the medial PFC (mPFC) is a key component of a large-scale neural system supporting a variety of self-related processes. However, it remains unknown whether the mPFC is critical for such processes. In this study, we used a human lesion approach to examine this question. We administered a standard trait judgment paradigm [Kelley, W. M., Macrae, C. N., Wyland, C. L., Caglar, S., Inati, S., & Heatherton, T. F. Finding the self? An event-related fMRI study. Journal of Cognitive Neuroscience, 14, 785–794, 2002] to patients with focal brain damage to the mPFC. The self-reference effect (SRE), a memory advantage conferred by self-related processing, served as a measure of intact self-processing ability. We found that damage to the mPFC abolished the SRE. The results demonstrate that the mPFC is necessary for the SRE and suggest that this structure is important for self-referential processing and the neural representation of self.

Preserved Self-Awareness following Extensive Bilateral Brain Damage to the Insula, Anterior Cingulate, and Medial Prefrontal Cortices

It has been proposed that self-awareness (SA), a multifaceted phenomenon central to human consciousness, depends critically on specific brain regions, namely the insular cortex, the anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC). Such a proposal predicts that damage to these regions should disrupt or even abolish SA. We tested this prediction in a rare neurological patient with extensive bilateral brain damage encompassing the insula, ACC, mPFC, and the medial temporal lobes. In spite of severe amnesia, which partially affected his “autobiographical self”, the patients SA remained fundamentally intact. His Core SA, including basic self-recognition and sense of self-agency, was preserved. His Extended SA and Introspective SA were also largely intact, as he has a stable self-concept and intact higher-order metacognitive abilities. The results suggest that the insular cortex, ACC and mPFC are not required for most aspects of SA. Our findings are compatible with the hypothesis that SA is likely to emerge from more distributed interactions among brain networks including those in the brainstem, thalamus, and posteromedial cortices.

Damage to the default mode network disrupts autobiographical memory retrieval

Functional neuroimaging studies have implicated the default mode network (DMN) in autobiographical memory (AM). Convergent evidence from a lesion approach would help clarify the role of the DMN in AM. In this study, we used a voxelwise lesion-deficit approach to test the hypothesis that regions of the DMN are necessary for AM. We also explored whether the neural correlates of semantic AM (SAM) and episodic AM (EAM) were overlapping or distinct. Using the Iowa Autobiographical Memory Questionnaire, we tested AM retrieval in 92 patients with focal, stable brain lesions. In support of our hypothesis, damage to regions within the DMN (medial prefrontal cortex, mPFC; posterior cingulate cortex, PCC; inferior parietal lobule, IPL; medial temporal lobe, MTL) was associated with AM impairments. Within areas of effective lesion coverage, the neural correlates of SAM and EAM were largely distinct, with limited areas of overlap in right IPL. Whereas SAM deficits were associated with left mPFC and MTL damage, EAM deficits were associated with right mPFC and MTL damage. These results provide novel neuropsychological evidence for the necessary role of parts of the DMN in AM. More broadly, the findings shed new light on how the DMN participates in self-referential processing.

Ventromedial prefrontal cortex mediates visual attention during facial emotion recognition

The ventromedial prefrontal cortex is known to play a crucial role in regulating human social and emotional behaviour, yet the precise mechanisms by which it subserves this broad function remain unclear. Whereas previous neuropsychological studies have largely focused on the role of the ventromedial prefrontal cortex in higher-order deliberative processes related to valuation and decision-making, here we test whether ventromedial prefrontal cortex may also be critical for more basic aspects of orienting attention to socially and emotionally meaningful stimuli. Using eye tracking during a test of facial emotion recognition in a sample of lesion patients, we show that bilateral ventromedial prefrontal cortex damage impairs visual attention to the eye regions of faces, particularly for fearful faces. This finding demonstrates a heretofore unrecognized function of the ventromedial prefrontal cortex-the basic attentional process of controlling eye movements to faces expressing emotion.

Ventromedial prefrontal cortex damage alters resting blood flow to the bed nucleus of stria terminalis

The ventromedial prefrontal cortex (vmPFC) plays a key role in modulating emotional responses, yet the precise neural mechanisms underlying this function remain unclear. vmPFC interacts with a number of subcortical structures involved in affective processing, including the amygdala, hypothalamus, periaqueductal gray, ventral striatum, and bed nucleus of stria terminalis (BNST). While a previous study of non-human primates shows that vmPFC lesions reduce BNST activity and anxious behavior, no such causal evidence exists in humans. In this study, we used a novel application of magnetic resonance imaging (MRI) in neurosurgical patients with focal, bilateral vmPFC damage to determine whether vmPFC is indeed critical for modulating BNST function in humans. Relative to neurologically healthy subjects, who exhibited robust rest-state functional connectivity between vmPFC and BNST, the vmPFC lesion patients had significantly lower resting-state perfusion of the right BNST. No such perfusion differences were observed for the amygdala, striatum, hypothalamus, or periaqueductal gray. This study thus provides unique data on the relationship between vmPFC and BNST, suggesting that vmPFC serves to promote BNST activity in humans. This finding is relevant for neural circuitry models of mood and anxiety disorders.

Subclinical depression severity is associated with distinct patterns of functional connectivity for subregions of anterior cingulate cortex

Depression is a prevalent psychiatric condition characterized by sad mood and anhedonia. Neuroscientific research has consistently identified abnormalities in a network of brain regions in major depression, including subregions of the anterior cingulate cortex (ACC). However, few studies have investigated whether the same neural correlates of depression symptom severity are apparent in subclinical or healthy subjects. In the current study, we used resting-state fMRI to examine functional connectivity for subregions of the ACC in N = 28 participants with subclinical levels of depression. In regression analyses, we examined relationships between depression severity and functional connectivity for pregenual ACC (pgACC), anterior subgenual ACC (sgACC), and posterior sgACC seed regions. Additionally, we examined relationships between ACC subregion connectivity and trait levels of positive and negative affect. We found distinct associations between depression severity and functional connectivity of ACC subregions. Higher depression severity was associated with reduced pgACC-striatum connectivity and reduced anterior sgACC-anterior insula connectivity. Consistent with resting-state findings in major depression, higher depression severity was also related to greater anterior sgACC-posterior cingulate connectivity and greater posterior sgACC-dorsolateral prefrontal connectivity. Lastly, there were distinct correlations between connectivity for anterior versus posterior ACC subregions and positive and negative affective traits. These findings provide novel support linking subclinical depression to the same neural substrates associated with major depression. More broadly, these results contribute to an emerging literature on dimensional approaches to psychiatric illness.

Ventromedial Prefrontal Cortex Lesions Alter Neural and Physiological Correlates of Anticipation

Uncertainty is a ubiquitous feature of our daily lives. Although previous studies have identified a number of neural and peripheral physiological changes associated with uncertainty, there are limited data on the causal mechanisms underlying these responses in humans. In this study, we address this empirical gap through a novel application of fMRI in neurosurgical patients with focal, bilateral ventromedial prefrontal cortex (vmPFC) damage. The fMRI task involved cued anticipation of aversive and neutral picture stimuli; “certain” cues unambiguously indicated the upcoming picture valence, whereas “ambiguous” cues could precede either picture type. Healthy subjects exhibited robust bilateral insula responses to ambiguous cues, and this cue-related insula activity significantly correlated with heart rate variability during the task. By contrast, the vmPFC lesion patients exhibited altered cue-related insula activity and reduced heart rate variability. These findings suggest a role for vmPFC in coordinating neural and physiological responses during anticipation.