Herpes simplex virus 1 infection and valacyclovir treatment in schizophrenia: Results from the VISTA study.

BACKGROUND: Several studies have implicated herpes simplex virus-type 1 (HSV-1) in the pathophysiology of schizophrenia. A recent trial demonstrated that the anti-viral medication valacylovir, which prevents replication of activated HSV-1, improved selected cognitive deficits in people with schizophrenia. In this study, we examined demographic and illness related differences between HSV-1 positive versus HSV-1 negative subjects with early phase schizophrenia and attempted to replicate the previous valacyclovir treatment results in this population. METHODS: 170 subjects with schizophrenia (HSV-1 positive N = 70; HSV-1 negative N = 96) from 12 US sites participated in the HSV-1 positive versus negative comparisons, and were randomized 1:1 to valacyclovir (1.5 g BID) or placebo for a 16-week, double-blind efficacy trial. The primary endpoints were working and verbal memory. RESULTS: The HSV-1 positive group, as compared to the HSV-1 negative group, were older (p < 0.001) with fewer males (p = 0.003), and had a longer duration of illness (p = 0.008), more positive symptoms (p = 0.013), poorer quality of life (p = 0.034) and more impairment on the letter-number sequencing test, which is a measure of working memory (p = 0.045). Valacyclovir failed to significantly improve any of the cognitive indices, symptom or functioning measures. CONCLUSIONS: HSV-1 sero-positivity appears to be a marker of a subgroup with a more severe form of schizophrenia. Valacyclovir was not efficacious in the study, perhaps because the herpes virus was in the dormant, non-activated state and therefore non-responsive to valacyclovir effects. ClinicalTrials.gov Identifier: NCT02008773.

Functional neuroanatomical correlates of episodic memory impairment in early phase psychosis.

Studies have demonstrated that episodic memory (EM) is often preferentially disrupted in schizophrenia. The neural substrates that mediate EM impairment in this illness are not fully understood. Several functional magnetic resonance imaging (fMRI) studies have employed EM probe tasks to elucidate the neural underpinnings of impairment, though results have been inconsistent. The majority of EM imaging studies have been conducted in chronic forms of schizophrenia with relatively few studies in early phase patients. Early phase schizophrenia studies are important because they may provide information regarding when EM deficits occur and address potential confounds more frequently observed in chronic populations. In this study, we assessed brain activation during the performance of visual scene encoding and recognition fMRI tasks in patients with earlyphase psychosis (n = 35) and age, sex, and race matched healthy control subjects (n = 20). Patients demonstrated significantly lower activation than controls in the right hippocampus and left fusiform gyrus during scene encoding and lower activation in the posterior cingulate, precuneus, and left middle temporal cortex during recognition of target scenes. Symptom levels were not related to the imaging findings, though better cognitive performance in patients was associated with greater right hippocampal activation during encoding. These results provide evidence of altered function in neuroanatomical circuitry subserving EM early in the course of psychotic illness, which may have implications for pathophysiological models of this illness.

Affect recognition, empathy, and dysosmia after traumatic brain injury.

OBJECTIVE: To investigate if olfaction is associated with affect recognition and empathy deficits after traumatic brain injury (TBI). Prior research has shown that TBI often leads to loss of smell. We hypothesized a relationship with emotion perception, because the neural substrates of the olfactory system overlap with the ventral circuitry of the orbital frontal cortex, which play a critical role in affective responses, such as empathy. DESIGN: Comparative study investigating differences between participants with TBI who had impaired olfaction (dysosmia) with those with normal olfaction (normosmia). SETTING: Postacute rehabilitation facilities in the United States, Canada, and New Zealand. PARTICIPANTS: Participants (N=106) in the current study were a convenience sample of adults with moderate to severe TBI who were tested for olfactory function as part of a larger, related study on affect recognition. On average, participants were 11.5 years postinjury. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Olfaction (Brief Smell Identification Test), facial affect recognition (Diagnostic Assessment of Nonverbal Affect 2-Adult Faces [DANVA2-AF]), vocal affect recognition (Diagnostic Assessment of Nonverbal Affect 2-Adult Paralanguage [DANVA2-AP]), emotional inference (Emotional Inference from Stories Test [EIST]), and empathy (Interpersonal Reactivity Index [IRI]). RESULTS: Fifty-six percent of participants were dysosmic and only 36% of these participants were aware of their deficit. Participants with dysosmia performed significantly poorer on the DANVA2-AF (P=.003), DANVA2-AP (P=.007), EIST (P=.016), and IRI (P=.013). Medium effect sizes were found for all measures. Dysosmia had a sensitivity value of 86.4% for detecting facial affect recognition impairments and 67.8% for vocal affect recognition impairments. CONCLUSIONS: This study shows that olfactory deficits may be indicative of affect recognition impairments and reduced empathy. Early knowledge of affect recognition and empathy deficits would be valuable so that treatment could be implemented predischarge.

Effects of alcohol availability, access to alcohol, and naltrexone on self-reported craving and patterns of drinking in response to an alcohol-cue availability procedure.

OBJECTIVE: Craving has long been cited by patients and providers as a principal construct in alcohol use disorders and an essential target for treatment. The goal of the current study was to examine the effects of alcohol availability (20% vs. 80% availability), access to alcohol ("open" vs. "locked" trials), and medication (oral naltrexone [Revia] vs. placebo) on self-reported craving and two behavioral measures of drinking (latency of attempt to access alcohol, amount of alcohol consumed when access permitted) in response to an alcohol-cue availability procedure. METHOD: Non-treatment-seeking, alcohol-dependent men and women (N = 58) self-referred for an alcohol administration study and were administered a modified alcohol-cue availability procedure under two medication conditions (naltrexone, placebo) using a within-subjects, repeated-measures design. RESULTS: Analyses demonstrated that the experimental manipulations used in this study had differential effects on craving and patterns of drinking. Specifically, reduced availability of alcohol (i.e., when alcohol was available in only 20% as opposed to 80% of trials) resulted in greater amounts of alcohol consumed per open trial; the unanticipated blocking of access to alcohol (i.e., a "locked" trial during the 80% availability condition) triggered more rapid attempts to obtain alcohol on subsequent trials. Naltrexone, relative to placebo, was associated with significant reductions in cravings for alcohol. CONCLUSIONS: Taken together, these findings offer partial support for the cognitive processing model and reinforce the utility of evaluating both self-report and behavioral indicators of motivation to drink in studies designed to identify factors associated with the construct of craving.

Involvement of the left anterior insula and frontopolar gyrus in odor discrimination.

Discriminating between successively presented odors requires brief storage of the first odor's perceptual trace, which then needs to be subsequently compared to the second odor in the pair. This study explores the cortical areas involved in odor discrimination and compares them with findings from studies of working-memory, traditionally investigated with n-back paradigms. Sixteen right-handed subjects underwent H(2) (15)O positron emission tomography during counterbalanced conditions of odorless sniffing, repeated single odor detection, multiple odor detection, and conscious successive discrimination between odor pairs. Eight odorants were delivered using a computer-controlled olfactometer through a birhinal nasal cannula. Conscious successive odor discrimination evoked significantly greater activity in the left anterior insula and frontopolar gyrus when compared to reported sensory detection of the identical odors. Additional activation was found in the left lateral orbital/inferior frontal and middle frontal gyri when discrimination was compared to the odorless condition. The left anterior insula is likely involved in the evaluation of odor properties. Consistent with other studies, frontopolar and middle frontal gyrus activation is more likely related to working memory during odor discrimination.

Neural correlates of olfactory change detection.

Detecting changes in a stream of sensory information is vital to animals and humans. While there have been several studies of automatic change detection in various sensory modalities, olfactory change detection is largely unstudied. We investigated brain regions responsive to both passive and active detection of olfactory change using fMRI. Nine right-handed healthy, normosmic subjects (five men) were scanned in two conditions while breathing in synchrony with a metronome. In one condition, subjects mentally counted infrequent odors (Attend condition), whereas in the other condition, subjects' attention was directed elsewhere as they counted auditory tones (Ignore condition). Odors were delivered via a nasal cannula using a computer-controlled air-dilution olfactometer. Infrequently occurring olfactory stimuli evoked significant (P < .05, corrected) activity in the subgenual cingulate and in central posterior orbitofrontal cortex, but only in the Ignore condition, as confirmed by direct comparison of the Ignore session with the Attend session (P < .05, corrected). Subgenual cingulate and posterior orbital cortex may therefore play a role in detecting discrepant olfactory events while attention is otherwise engaged in another sensory modality.

Alcohol-related olfactory cues activate the nucleus accumbens and ventral tegmental area in high-risk drinkers: preliminary findings.

BACKGROUND: The mesocorticolimbic dopamine system is implicated in motivation and reward and may be involved in the development of alcoholism. METHODS: We used functional magnetic resonance imaging to study the blood oxygen level-dependent (BOLD) response to alcohol-related olfactory stimuli (AROS; odors of beer and whiskey) and non-alcohol-related olfactory stimuli (NAROS; odors of grass and leather) in 10 high-risk (HR) drinkers (average drinks per week, 19.99; SD, 6.99; all with > or = 2 first- or second-degree alcoholic relatives) and 5 low-risk (LR) social drinking controls (drinks per week, 2.82; SD, 2.87; 1 subject had 1 second-degree alcoholic relative). Data were analyzed with SPM99 and random effects analysis by using regions of interest and corrected cluster statistics (p < 0.05) to focus on the nucleus accumbens (NAc) and ventral tegmental area (VTA). RESULTS: In HR subjects, there was a greater BOLD signal increase in the NAc during AROS than during clean air. BOLD signal increases during AROS were also greater in the NAc than the signal increases induced by NAROS. The AROS signal was significantly greater than the NAROS signal in a small number of voxels in the VTA. Finally, the AROS/NAROS difference signal was larger in HR drinkers in both the NAc and VTA. CONCLUSIONS: Alcoholic olfactory cues may invoke the dopaminergic mesocorticolimbic system to a greater degree than nonalcoholic odors and could be effective tools in exploring the role of the dopamine system in susceptibility to alcoholism.

Olfactory system activation from sniffing: effects in piriform and orbitofrontal cortex.

Neuroimaging studies suggest that piriform cortex is activated at least in part by sniffing. We used H(2)(15)O positron emission tomography (PET) to study 15 healthy volunteers while they participated in four conditions, two of which were sniffing odorants and odorless air. The remaining two conditions involved a constant, very low flow of either odorized or odorless air during velopharyngeal closure (VPC), a technique that prevents subject-induced airflow through the nasal passages. Contrary to expectation, sniffing under odorless conditions did not induce significant piriform and surrounding cortical (PC+) activity when compared to odorless VPC, even at a liberal statistical threshold. However, a small correlation emerged in PC+ between the difference signal of [odorless sniffing - odorless VPC] and peak rate of nasal pressure change. PC+ activity was, however, strongly evoked by odorant exposure during sniffing and VPC, with neither technique showing greater activation. Activity in orbitofrontal (olfactory association) cortex was absent during odorant stimulation (OS) with VPC, but present during odorant sniffing. Sniffing may therefore play an important role in facilitating the higher-order analysis of odors. A right orbitofrontal region was also activated with odorless sniffing, which suggests a possible orbitofrontal role in guided olfactory exploration.

Plasma constituents and mortality in rat pups given chronic insulin via injection, pellet, or osmotic minipump.

Two studies compared the glucose responses of 9-day-old rats given subcutaneous insulin, either continuously or via daily injection, for 10 days. In Experiment 1, implanted pellets released a total of 0, 1.9, or 5.7 U insulin/kg the first 24 h. Injected doses were larger, 0 or 8 U/kg. Injections caused no deaths, but insulin-releasing pellets caused high mortality within 24 h. Pups surviving the pellets were normoglycemic by treatment day 8. In Experiment 2, pups received 0.184 U of insulin daily, approximately 8 U/kg at 9 days, via either injection or osmotic minipump. All pups survived. Injected pups were hypoglycemic 2 h postinjection through treatment day 10, whereas pups with insulin minipumps were normoglycemic by day 5. Insulin injections, but not minipumps, lowered plasma triglycerides on day 10. To examine age differences in response to insulin, additional pups and adults received daily injections of 0 or 8 U/kg for 10 days. All survived. Insulin lowered plasma glucose more in pups than in adults and reduced triglycerides in pups but not in adults. The rapid development of normoglycemia in pups with insulin minipumps, compared with pups injected daily with the same dose, suggests that continuous early insulin may produce insulin resistance.