Anthony P. Weiss

Increased medial temporal lobe activation during the passive viewing of emotional and neutral facial expressions in schizophrenia

INTRODUCTION Patients with schizophrenia show deficits in facial affect and facial identity recognition and exhibit structural and neurophysiological abnormalities in brain regions known to mediate these processes. Functional neuroimaging studies of neural responses to emotional facial expressions in schizophrenia have reported both increases and decreases in medial temporal lobe (MTL) activity in schizophrenia. Some of this variability may be related to the tasks performed and the baseline conditions used. Here we tested whether MTL responses to human faces in schizophrenia are abnormal when unconstrained by a cognitive task and measured relative to a low-level baseline (fixation) condition. METHODS 15 patients with schizophrenia and 16 healthy control subjects underwent functional magnetic resonance imaging (fMRI) while passively viewing human faces displaying fearful, happy, and neutral emotional expressions. RESULTS Relative to control subjects, the patients demonstrated (1) significantly greater activation of the left hippocampus while viewing all three facial expressions and (2) increased right amygdala activation during the initial presentation of fearful and neutral facial expressions. CONCLUSIONS In schizophrenia, hippocampal and amygdala activity is elevated during the passive viewing of human faces.

The Effects of Transdermal Nicotine on Cognition in Nonsmokers with Schizophrenia and Nonpsychiatric Controls

Abundant evidence indicates that the neuronal nicotinic acetylcholine receptor (nAChR) system is integral to regulation of attentional processes and is dysregulated in schizophrenia. Nicotinic agonists may have potential for the treatment of cognitive impairment in this disease. This study investigated the effects of transdermal nicotine on attention in individuals with schizophrenia (n=28) and healthy controls (n=32). All participants were nonsmokers in order to eliminate confounding effects of nicotine withdrawal and reinstatement that may occur in the study of smokers. Subjects received 14 mg transdermal nicotine and identical placebo in a randomized, placebo-controlled, crossover design. A cognitive battery was conducted before and 3 h after each patch application. The primary outcome measure was performance on the Continuous Performance Test Identical Pairs (CPT-IP) Version. Nicotine significantly improved the performance on the CPT-IP as measured by hit reaction time, hit reaction time standard deviation and random errors in both groups. In addition, nicotine reduced commission errors on the CPT-IP and improved the performance on a Card Stroop task to a greater extent in those with schizophrenia vs controls. In summary, nicotine improved attentional performance in both groups and was associated with greater improvements in inhibition of impulsive responses in subjects with schizophrenia. These results confirm previous findings that a single dose of nicotine improves attention and suggest that nicotine may specifically improve response inhibition in nonsmokers with schizophrenia.

Impaired hippocampal recruitment during normal modulation of memory performance in schizophrenia

BACKGROUND Patients with schizophrenia demonstrate poor verbal memory, ascribed to impaired prefrontal and hippocampal function. Healthy adults can increase recall accuracy following encoding interventions, such as item repetition and the formation of semantic associations. We examined the effects of these interventions on both memory performance and retrieval-related hippocampal activity in healthy adults and patients with schizophrenia. METHODS Twelve patients with schizophrenia and twelve healthy control subjects participated. During study, subjects counted either the number of meanings or T-junctions in words seen only once or repeated four times. At test, O15-positron emission tomography scans were acquired while subjects completed word-stems with previously studied items. RESULTS Control subjects recalled more words overall, but both groups demonstrated similar performance benefits following deeper encoding. Both item repetition and the use of a semantic encoding task were associated with memory retrieval-related hippocampal recruitment in control but not schizophrenic participants. Patients with schizophrenia demonstrated greater activation of prefrontal cortical areas during word retrieval. CONCLUSIONS Despite a lack of hippocampal recruitment, patients with schizophrenia showed intact modulation of memory performance following both encoding interventions. Impaired hippocampal recruitment, in concert with greater prefrontal activation, may reflect a specific deficit in conscious recollection in schizophrenia.

Neuroimaging of declarative memory in schizophrenia

The past three decades have seen tremendous growth in our understanding of the cerebral underpinnings of schizophrenia. including the neural correlates of the cognitive impairment seen in this syndrome. In this article we review the role that structural and functional neuroimaging has played in elucidating the cerebral basis for the declarative memory deficits associated with schizophrenia. Memory impairment in schizophrenia appears to involve abnormal connectivity between the prefrontal cortex and three regions important in normal learning and memory: the hippocampus, thalamus, and cerebellum.

Sustained activation of the hippocampus in response to fearful faces in schizophrenia

BACKGROUND In healthy individuals, the activity of the medial temporal lobe habituates rapidly with the repeated presentation of a stimulus. Using functional magnetic resonance imaging (fMRI), we tested the hypothesis that habituation of the medial temporal lobe is reduced in schizophrenia. METHODS During fMRI scanning, fearful and happy faces were presented repeatedly to healthy control subjects (n =16) and patients with schizophrenia (n =18). Habituation of medial temporal lobe structures was measured by comparing the hemodynamic response occurring during the early and late portions of the presentation of each face. RESULTS Control subjects demonstrated significant medial temporal lobe habituation to fearful but not to happy faces. In contrast, patients with schizophrenia did not demonstrate medial temporal lobe habituation in response to fearful or happy faces. In a direct, between-group comparison, right hippocampal habituation to fearful faces was significantly greater in control subjects than in the schizophrenia patients. Also, there were no significant differences between the patients and control subjects in the early medial temporal lobe response to fearful faces, suggesting that attenuated hippocampal habituation in schizophrenia is not associated with a reduction in initial activation. CONCLUSIONS These findings suggest that there is abnormal modulation of hippocampal responses to fearful faces in schizophrenia.

Neuroimaging of hallucinations: a review of the literature

While hallucinations have been described for over two millennia, their cause remains unclear. Brain-based models suggest that abnormal cerebral excitation and a lack of normal cerebral inhibition may play primary roles, but evaluation of these hypotheses has been hampered by difficulty in studying the hallucinatory state. Recent advances in neuroimaging have provided researchers with tools to study a variety of mental states, including hallucinations. We review the literature regarding the structural and functional neural correlates of hallucinations. Despite small sample sizes and methodological differences, several studies describe similar results: hallucinations are associated with sensory modality-specific activation in cerebral areas involved in normal sensory processing. Furthermore, neural activation may be specifically related to distinct phenomenological features of the hallucinatory experience. Further work is needed to better understand the neural basis of hallucinations.

Anterior and posterior hippocampal volumes in schizophrenia

BACKGROUND While the evidence for hippocampal structural abnormalities in schizophrenia is now well accepted, whether there is differentially greater volume loss within specific subregions of the hippocampus remains a matter of some debate. Here we present volume estimates of anterior and posterior hippocampal volumes using a novel morphometric protocol. METHODS We studied 25 male patients with schizophrenia and 25 age-matched male control subjects. Hippocampal volumes were estimated using a three-dimensional morphometric protocol for the analysis of high-resolution structural magnetic resonance images (MRI). Anterior hippocampal volumes were differentiated from posterior hippocampal volumes by the presence of the uncus in coronal slices. RESULTS While the patients with schizophrenia had significantly smaller overall hippocampal volumes relative to the control group, there was no evidence for a topographically specific pattern of volume loss along the anterior-posterior hippocampal axis. CONCLUSIONS These results confirm the presence of overall hippocampal volume decreases in patients with schizophrenia, but do not confirm a topographically specific localization of this effect. It appears that the hippocampal volume deficit in schizophrenia is diffuse, a finding that has important consequences for understanding the underlying pathophysiologic mechanisms in schizophrenia.

MTHFR 677C --> T genotype disrupts prefrontal function in schizophrenia through an interaction with COMT 158Val --> Met.

Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val → Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val → Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C → T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR × COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.

Magnetic Resonance Imaging-guided Stereotactic Limbic Leukotomy for Treatment of Intractable Psychiatric Disease

OBJECTIVE To assess the efficacy and complication rates of magnetic resonance imaging-guided stereotactic limbic leukotomy for the treatment of intractable major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). METHODS We conducted preoperative evaluations and postoperative follow-up assessments of efficacy and complications for 21 patients who underwent limbic leukotomy. Efficacy was based on physician- and patient-rated global assessments of functioning, as well as evaluations using disease-specific rating scales commonly used in studies of MDD and OCD. RESULTS The mean time from limbic leukotomy to follow-up assessment was 26 months. On the basis of standard outcome measures, 36 to 50% of patients were considered to be treatment responders. Although permanent surgical morbidity was rare, there were reports of postoperative sequelae, including apathy, urinary incontinence, and memory complaints, which occurred in a substantial minority of cases. CONCLUSION For this cohort of 21 patients with chronic severe MDD or OCD, who had experienced failure with an exhaustive array of previous treatments, limbic leukotomy was associated with substantial benefit for 36 to 50%. This rate is comparable to those of previous studies of limbic system surgery and indicates that limbic leukotomy is a feasible treatment option for severe, treatment-refractory MDD or OCD. Adverse consequences associated with the procedure included affective, cognitive, and visceromotor sequelae, which were generally transient.

Impaired Hippocampal Function During the Detection of Novel Words in Schizophrenia

BACKGROUND Patients with schizophrenia have smaller hippocampal volumes and perform abnormally on most declarative memory tasks. Although these findings are likely related, the impact of hippocampal pathology on cognitive performance in schizophrenia remains unclear. This study examined this relationship by measuring the volume of the hippocampus and its activation during memory task performance. METHODS Participants included 15 patients with schizophrenia and 16 age-matched control subjects. Hippocampal volume was determined via three-dimensional volumetric analysis of high-resolution magnetic resonance images. Hippocampal activity was assessed by measuring changes in blood oxygen level-dependent signal during a recognition memory task. RESULTS Patients with schizophrenia had smaller hippocampal volumes bilaterally and demonstrated poorer performance on the recognition memory task, largely because of a heightened rate of false alarms to novel stimuli. Both groups showed robust hippocampal activity to old and new items when compared with a low-level baseline task; however, direct comparison of hippocampal activity during recognition task performance revealed that healthy control, but not the schizophrenia, subjects showed significant right anterior hippocampal activation during the evaluation of novel items. CONCLUSIONS The impaired ability to classify new items as previously not experienced is associated with decreased recruitment and smaller volume of the hippocampus in schizophrenia.