Faculty Bibliography

Objective: Aggression in schizophrenia is a major societal issue, leading to physical harm, stigmatization, patient distress, and higher health care costs. Impulsivity is associated with aggression in schizophrenia, but it is multidetermined. The subconstruct of urgency is likely to play an important role in this aggression, with positive urgency referring to rash action in the context of positive emotion, and negative urgency referring to rash action in the context of negative emotion. Method: The authors examined urgency and its neural correlates in 33 patients with schizophrenia or schizoaffective disorder and 31 healthy comparison subjects. Urgency was measured using the Urgency, Premeditation, Perseverance, and Sensation-Seeking scale. Aggressive attitudes were measured using the Buss-Perry Aggression Questionnaire. Results: Positive urgency, negative urgency, and aggressive attitudes were significantly and selectively elevated in schizophrenia patients (Cohen's d values, 1.21-1.50). Positive and negative urgency significantly correlated with the Aggression Questionnaire total score (r>0.48 in all cases) and each uniquely accounted for a significant portion of the variance in aggression over and above the effect of group. Urgency scores correlated with reduced cortical thickness in ventral prefrontal regions including the right frontal pole, the medial and lateral orbitofrontal gyrus and inferior frontal gyri, and the rostral anterior cingulate cortex. In patients, reduced resting-state functional connectivity in some of these regions was associated with higher urgency. Conclusions: These findings highlight the key role of urgency in aggressive attitudes in people with schizophrenia and suggest neural substrates of these behaviors. The results also suggest behavioral and neural targets for interventions to remediate urgency and aggression.

BACKGROUND:Intact sarcasm perception is a crucial component of social cognition and mentalizing (the ability to understand the mental state of oneself and others). In sarcasm, tone of voice is used to negate the literal meaning of an utterance. In particular, changes in pitch are used to distinguish between sincere and sarcastic utterances. Schizophrenia patients show well-replicated deficits in auditory function and functional connectivity (FC) within and between auditory cortical regions. In this study we investigated the contributions of auditory deficits to sarcasm perception in schizophrenia. METHOD/METHODS:Auditory measures including pitch processing, auditory emotion recognition (AER) and sarcasm detection were obtained from 76 patients with schizophrenia/schizo-affective disorder and 72 controls. Resting-state FC (rsFC) was obtained from a subsample and was analyzed using seeds placed in both auditory cortex and meta-analysis-defined core-mentalizing regions relative to auditory performance. RESULTS:Patients showed large effect-size deficits across auditory measures. Sarcasm deficits correlated significantly with general functioning and impaired pitch processing both across groups and within the patient group alone. Patients also showed reduced sensitivity to alterations in mean pitch and variability. For patients, sarcasm discrimination correlated exclusively with the level of rsFC within primary auditory regions whereas for controls, correlations were observed exclusively within core-mentalizing regions (the right posterior superior temporal gyrus, anterior superior temporal sulcus and insula, and left posterior medial temporal gyrus). CONCLUSIONS:These findings confirm the contribution of auditory deficits to theory of mind (ToM) impairments in schizophrenia, and demonstrate that FC within auditory, but not core-mentalizing, regions is rate limiting with respect to sarcasm detection in schizophrenia.

Patients with schizophrenia exhibit cognitive and sensory impairment, and object recognition deficits have been linked to sensory deficits. The "frame and fill" model of object recognition posits that low spatial frequency (LSF) information rapidly reaches the prefrontal cortex (PFC) and creates a general shape of an object that feeds back to the ventral temporal cortex to assist object recognition. Visual dysfunction findings in schizophrenia suggest a preferential loss of LSF information. This study used functional magnetic resonance imaging (fMRI) and resting state functional connectivity (RSFC) to investigate the contribution of visual deficits to impaired object "framing" circuitry in schizophrenia. Participants were shown object stimuli that were intact or contained only LSF or high spatial frequency (HSF) information. For controls, fMRI revealed preferential activation to LSF information in precuneus, superior temporal, and medial and dorsolateral PFC areas, whereas patients showed a preference for HSF information or no preference. RSFC revealed a lack of connectivity between early visual areas and PFC for patients. These results demonstrate impaired processing of LSF information during object recognition in schizophrenia, with patients instead displaying increased processing of HSF information. This is consistent with findings of a preference for local over global visual information in schizophrenia.

BACKGROUND: Apathy is common in late-life depression and is associated with disability and poor antidepressant response. This study examined whether resting functional connectivity (FC) of the nucleus accumbens (NAcc) and the dorsal anterior cingulate (dACC) with other structures can distinguish apathetic depressed older patients from non-apathetic depressed patients and normal subjects. METHODS: Twenty-six non-demented, non-MCI older adults were studied. Of these, 16 had major depression (7 also had apathy) and 10 had no psychopathology. Resting state fMRI was performed prior to treatment in subjects who were psychotropic-free for at least two weeks. FC was determined by placing seeds in the NAcc and the dACC bilaterally. RESULTS: Apathetic depressed patients had lower FC of the NAcc with the amygdala, caudate, putamen, globus pallidus, and thalamus and increased FC with the dorsomedial prefrontal cortex, the superior frontal cortex, and the insula than non-apathetic patients. Further, apathetic patients had lower FC of the dACC with dorsolateral and ventrolateral prefrontal cortices and higher FC with the insula and the orbitofrontal cortex than non-apathetic patients. LIMITATIONS: Small number of subjects, lack of random sampling, use of a 1.5T MRI scanner. CONCLUSIONS: This preliminary study suggests that FC between the NAcc and the dACC and structures related to reward and related behavioral responses constitute the functional topography of abnormalities characterizing apathy of late life depression. However, replication is needed.

Although many resting state fMRI human studies have been published, the number of such rodent studies is considerably less. The reason for this is the severe technical challenge of high magnetic field small rodent imaging. Local magnetic field susceptibility changes at air tissue boundaries cause image distortion and signal losses. The current study reports measures of functional connectivity in mice using only isoflurane for the anesthetic. Because all anesthetic agents will alter cerebral blood flow and cerebral metabolism, the impact these changes have on neuronal connectivity has yet to be fully understood, however this work reports for the first time that reliable functional connectivity measures in mouse brain can be obtained with isoflurane.

Perception has been identified by the NIMH-sponsored Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) group as a useful domain for assessing cognitive deficits in patients with schizophrenia. Specific measures of contrast gain derived from recordings of steady-state visual evoked potentials (ssVEP) have demonstrated neural deficits within the visual pathways of patients with schizophrenia. Psychophysical measures of contrast sensitivity have also shown functional loss in these patients. In the current study, functional magnetic resonance imaging (fMRI) was used in conjunction with ssVEP and contrast sensitivity testing to elucidate the neural underpinnings of these deficits. During fMRI scanning, participants viewed 1) the same low and higher spatial frequency stimuli used in the psychophysical contrast sensitivity task, at both individual detection threshold contrast and at a high contrast; and 2) the same stimuli used in the ssVEP paradigm, which were designed to be biased toward either the magnocellular or parvocellular visual pathway. Patients showed significant impairment in contrast sensitivity at both spatial frequencies in the psychophysical task, but showed reduced occipital activation volume for low, but not higher, spatial frequency at the low and high contrasts tested in the magnet. As expected, patients exhibited selective deficits under the magnocellular-biased ssVEP condition. However, occipital lobe fMRI responses demonstrated the same general pattern for magnocellular- and parvocellular-biased stimuli across groups. These results indicate dissociation between the fMRI measures and the psychophysical/ssVEP measures. These latter measures appear to have greater value for the functional assessment of the contrast deficits explored here.

Schizophrenia has been increasingly conceptualized as a disorder of brain connectivity, in large part due to findings emerging from white matter and functional connectivity (FC) studies. This work has focused primarily on within-hemispheric connectivity, however some evidence has suggested abnormalities in callosal structure and interhemispheric interaction. Here we examined functional connectivity between homotopic points in the brain using a technique called voxel-mirrored homotopic connectivity (VMHC). We performed VMHC analyses on resting state fMRI data from 23 healthy controls and 25 patients with schizophrenia or schizoaffective disorder. We found highly significant reductions in VMHC in patients for a number of regions, particularly the occipital lobe, the thalamus, and the cerebellum. No regions of increased VMHC were detected in patients. VMHC in the postcentral gyrus extending into the precentral gyrus was correlated with PANSS Total scores. These results show substantial impairment of interhemispheric coordination in schizophrenia.

BACKGROUND: Abnormalities have been identified in the Cognitive Control Network (CCN) and the Default Mode Network (DMN) during episodes of late-life depression. This study examined whether functional connectivity at rest (FC) within these networks characterizes late-life depression and predicts antidepressant response. METHODS: 26 non-demented, non-MCI older adults were studied. Of these, 16 had major depression and 10 had no psychopathology. Depressed patients were treated with escitalopram (target dose 20mg) for 12weeks after a 2-week placebo phase. Resting state time series was determined prior to treatment. FC within the CCN was determined by placing seeds in the dACC and the DLPFC bilaterally. FC within the DMN was assessed from a seed placed in the posterior cingulate. RESULTS: Low resting FC within the CCN and high resting FC within the DMN distinguished depressed from normal elderly subjects. Beyond this "double dissociation", low resting FC within the CCN predicted low remission rate and persistence of depressive symptoms and signs, apathy, and dysexecutive behavior after treatment with escitalopram. In contrast, resting FC within the DMN was correlated with pessimism but did not predict treatment response. CONCLUSIONS: If confirmed, these findings may serve as a signature of the brain's functional topography characterizing late-life depression and sustaining its symptoms. By identifying the network abnormalities underlying biologically meaningful characteristics (apathy, dysexecutive behavior, pessimism) and sustaining late-life depression, these findings can provide a novel target on which new somatic and psychosocial treatments can be tested.