Neuroimaging of frontal-limbic dysfunction in schizophrenia and epilepsy-related psychosis: toward a convergent neurobiology

Abstract

Psychosis is a devastating, prevalent condition considered to involve dysfunction of frontal and medial temporal limbic brain regions as key nodes in distributed brain networks involved in emotional regulation. The psychoses of epilepsy represent an important, though understudied, model relevant to understanding the pathophysiology of psychosis in general. In this review, we (1) discuss the classification of epilepsy-related psychoses and relevant neuroimaging and other studies; (2) review structural and functional neuroimaging studies of schizophrenia focusing on evidence of frontal-limbic dysfunction; (3) report our laboratory's PET, fMRI, and electrophysiological findings; (4) describe a theoretical framework in which frontal hypoactivity and intermittent medial temporal hyperactivity play a critical role in the etiopathology of psychosis both associated and unassociated with epilepsy; and (5) suggest avenues for future research.

Figure 1

Areas of decreased blood flow measured using H2150 PET in an unmedicated patient during the experience of auditory and visual hallucinations (p<.01). 1A. Axial and 1B mid-sagittal views showing decreased blood flow in right rostral prefrontal and ventromedial prefrontal cortices as well as in left dorsolateral prefrontal subcortical region. See [59] for methodological details and for areas of increased blood flow during hallucinations.

Figure 2

Statistical Parametric Map (SPM) of differences of blood flow measured using H2150 PET (p<.01). 2A. Threat vs. Neutral words in healthy controls (from [52]). Note bilateral amygdalar activation in normal subjects in response to threat. 2B. Paranoid (n=6) vs. non-paranoid (n=4) patients during presentation of neutral words. In paranoid patients, left periamygdalar activity (as well as bilateral visual association cortex) is evoked inappropriately by neutral stimuli.

Figure 3

Statistical parametric map (SPM) of BOLD fMRI activity late during an experimental condition of safety, when participants have been told that they are NOT in danger of receiving electrodermal stimulation (thresholded at t=2). 3A. Actively paranoid schizophrenic patients (n=6) have greater activity in the right hippocampal/parahippocampal region as compared to healthy controls (n=18). 3B. In schizophrenic patients with varying levels of paranoia (n=23), bilateral ventral hippocampal activity during the late safety condition correlates with level of paranoia (assessed by PANSS).

Figure 4

Thresholded (p<.001) time frequency spectrogram of average left medial temporal response to viewing negative (frightened) face pictures. Faces are presented at time 0. Post-stimulus activity is compared statistically to a pre-stimulus baseline. 4A. Subject #1, a representative psychiatrically healthy patient, shows expected increased gamma (80–100 Hz) activity .2 – .8 seconds after negative face presentation. 4B. Subject #2, a patient with schizophrenia-like psychosis of epilepsy and chronic paranoia, shows decreased gamma and high-gamma activity following stimulus presentation, suggesting aberrant medial temporal response to threat.