Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia.

BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. METHODS: Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. RESULTS: 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude. CONCLUSION: Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

Theatre improvisation training to promote social cognition: A novel recovery-oriented intervention for youths at clinical risk for psychosis.

AIM: Few interventions address social cognition or functioning in individuals at clinical risk (CR) for psychosis. Theatre Improvisation Training to Promote Social Cognition (TIPS) is a manualized intervention based on drama therapy. We aim to describe TIPS, evaluate feasibility and acceptability, and present a preliminary investigation of outcomes in a quasi-experimental design. METHODS: Thirty-six CR participants (15-25 years) were ascertained from the Philadelphia Neurodevelopmental Cohort. Twenty-six completed the TIPS protocol: 18 weekly 2-hour group sessions led by a theatre director and actor-assistant. Participants engaged in collaborative acting and improvisation exercises. Baseline and follow-up assessments included the Clinical Assessment Interview for Negative Symptoms (CAINS), Structured Interview for Prodromal Syndromes, Global Assessment of Functioning (GAF) and Penn Computerized Neurocognitive Battery (CNB), which includes social cognitive tests. Acceptability was assessed using focus groups. Preliminary outcomes were compared to CR controls who were not enrolled in the study but completed follow-up assessments using the same methods. RESULTS: There were no significant differences in baseline demographics, psychosis symptoms, or cognition between those who did and did not complete the protocol. Overall, TIPS was considered feasible and acceptable among CR. Preliminary outcomes suggest that TIPS may be effective in improving positive and negative psychosis-spectrum symptoms and GAF, but not performance on facial emotion processing. CONCLUSIONS: TIPS is a promising and acceptable intervention that may improve symptoms and functioning in CR while providing a framework for participants to develop more empowered and confident ways of relating to others. Larger randomized controlled trials investigating TIPS efficacy are warranted.

Randomized Controlled Trial of Imagery Rehearsal for Posttraumatic Nightmares in Combat Veterans.

STUDY OBJECTIVES: To examine the efficacy of imagery rehearsal (IR) combined with cognitive behavioral therapy for insomnia (CBT-I) compared to CBT-I alone for treating recurrent nightmares in military veterans with posttraumatic stress disorder (PTSD). METHODS: In this randomized controlled study, 108 male and female United States veterans of the Iraq and Afghanistan conflicts with current, severe PTSD and recurrent, deployment-related nightmares were randomized to six sessions of IR + CBT-I (n = 55) or CBT-I (n = 53). Primary outcomes were measured with the Nightmare Frequency Questionnaire (NFQ) and Nightmare Distress Questionnaire (NDQ). RESULTS: Improvement with treatment was significant (29% with reduction in nightmare frequency and 22% with remission). Overall, IR + CBT-I was not superior to CBT-I (NFQ: -0.12; 95% confidence interval = -0.87 to 0.63; likelihood ratio chi square = 4.7(3), P = .2); NDQ: 1.5, 95% confidence interval = -1.4 to 4.4; likelihood ratio chi square = 7.3, P = .06). CONCLUSIONS: Combining IR with CBT-I conferred no advantage overall. Further research is essential to examine the possibly greater benefit of adding IR to CBT-I for some subgroups of veterans with PTSD. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Cognitive Behavioral Therapy (CBT) for Nightmares in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans; Identifier: NCT00691626; URL: https://clinicaltrials.gov/ct2/show/NCT00691626.

Association of Prenatal Exposure to Population-Wide Folic Acid Fortification With Altered Cerebral Cortex Maturation in Youths.

Importance: Presently, 81 countries mandate the fortification of grain products with folic acid to lessen the risk of neural tube defects in the developing fetus. Epidemiologic data on severe mental illness suggest potentially broader effects of prenatal folate exposure on postnatal brain development, but this link remains unsubstantiated by biological evidence. Objective: To evaluate associations among fetal folic acid exposure, cortical maturation, and psychiatric risk in youths. Design, Setting, and Participants: A retrospective, observational clinical cohort study was conducted at Massachusetts General Hospital (MGH) among 292 youths 8 to 18 years of age born between January 1993 and December 2001 (inclusive of folic acid fortification rollout ±3.5 years) with normative results of clinical magnetic resonance imaging, divided into 3 age-matched groups based on birthdate and related level of prenatal folic acid fortification exposure (none, partial, or full). Magnetic resonance imaging was performed between January 2005 and March 2015. Two independent, observational, community-based cohorts (Philadelphia Neurodevelopmental Cohort [PNC] and National Institutes of Health Magnetic Resonance Imaging Study of Normal Brain Development [NIH]) comprising 1078 youths 8 to 18 years of age born throughout (PNC, 1992-2003) or before (NIH, 1983-1995) the rollout of folic acid fortification were studied for replication, clinical extension, and specificity. Statistical analysis was conducted from 2015 to 2018. Exposures: United States-mandated grain product fortification with folic acid, introduced in late 1996 and fully in effect by mid-1997. Main Outcomes and Measures: Differences in cortical thickness among nonexposed, partially exposed, and fully exposed youths (MGH) and underlying associations between age and cortical thickness (all cohorts). Analysis of the PNC cohort also examined the association of age-cortical thickness slopes with the odds of psychotic symptoms. Results: The MGH cohort (139 girls and 153 boys; mean [SD] age, 13.3 [2.3] years) demonstrated exposure-associated cortical thickness increases in bilateral frontal and temporal regions (9.9% to 11.6%; corrected P < .001 to P = .03) and emergence of quadratic (delayed) age-associated thinning in temporal and parietal regions (ß = -11.1 to -13.9; corrected P = .002). The contemporaneous PNC cohort (417 girls and 444 boys; mean [SD] age, 13.5 [2.7] years) also exhibited exposure-associated delays of cortical thinning (ß = -1.59 to -1.73; corrected P < .001 to P = .02), located in similar regions and with similar durations of delay as in the MGH cohort. Flatter thinning profiles in frontal, temporal, and parietal regions were associated with lower odds of psychosis spectrum symptoms in the PNC cohort (odds ratio, 0.37-0.59; corrected P < .05). All identified regions displayed earlier thinning in the nonexposed NIH cohort (118 girls and 99 boys; mean [SD] age, 13.3 [2.6] years). Conclusions and Relevance: The results of this study suggest an association between gestational exposure to fortification of grain products with folic acid and altered cortical development and, in turn, with reduction in the risk of psychosis in youths.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Don't worry, be happy - Neural correlates of the influence of musically induced mood on self-evaluation.

Self-evaluation affects one's own mental state, social interactions and everyday life. Mood, in turn, has an impact on self-evaluation. However, the influence of mood on self-evaluation at the neural level has barely been examined. In this fMRI study, the interaction of mood and self-perception was investigated in 20 healthy participants. Happy, sad and neutral music was presented while participants were instructed to immerse themselves in the mood of the music and to rate how well presented traits characterized themselves. In a lexical control condition, subjects had to count a specific letter in the word. Behavioral data reflected successful mood induction. While self-ascription of positive traits was unaffected by mood, self-ascription of negative characteristics was decreased by negative affect. A positive correlation was found between self-worth scores and the difference in the amount of self-ascribed positive versus negative traits during negative mood induction. At the neural level, amygdalo-hippocampal, superior and middle temporal structures were differently involved in self-evaluation (vs. lexical processing) depending on the mood. While activation of the amygdalo-hippocampal complex was found during sad in comparison to both happy and neutral mood, superior/middle temporal gyrus (STG/MTG) activation was only found when contrasting sad vs. neutral mood. Further, a correlation analysis with self-worth ratings revealed a positive relation to STG activation during self-ascription of trait adjectives in sad compared to neutral mood. Our results underscore the importance of the current emotional state for self-evaluation and identify some neural correlates of this effect. Our findings in healthy research participants suggest a compensatory mechanism during sad mood induction to maintain a positive self-image, which is supported by activation of limbic and fronto-temporal cortex. Studies in clinically depressed populations could reveal whether this compensatory mechanism is aberrant.

Verbal memory functioning moderates psychotherapy treatment response for PTSD-Related nightmares.

Posttraumatic stress disorder (PTSD) is associated with cognitive deficits in attention, executive control, and memory, although few studies have investigated the relevance of cognitive difficulties for treatment outcomes. We examined whether cognitive functioning and history of traumatic brain injury (TBI) were associated with response to cognitive-behavioral therapy (CBT) for PTSD-related sleep problems. In a randomized controlled trial of Imagery Rehearsal (IR) added to components of CBT for Insomnia (IR + cCBT-I) compared to cCBT-I alone for PTSD-related recurrent nightmares, 94 U.S. veterans completed a battery of cognitive tests. TBI was assessed via structured clinical interview. Mixed-effects models examined main effects of cognitive functioning and interactions with time on primary sleep and nightmare outcomes. Significant verbal immediate memory by time interactions were found for nightmare distress, nightmare frequency, and sleep quality, even after controlling for overall cognitive performance and depression. TBI exhibited main effects on outcomes but no interactions with time. Findings indicated that individuals with lower verbal memory performance were less likely to respond to treatment across two sleep interventions. Veterans with TBI displayed greater symptoms but no altered trajectories of treatment response. Together with prior literature, findings suggest that verbal memory functioning may be important to consider in PTSD treatment implementation.

A randomised controlled trial of adjunctive yoga and adjunctive physical exercise training for cognitive dysfunction in schizophrenia.

BACKGROUND: Yoga and physical exercise have been used as adjunctive intervention for cognitive dysfunction in schizophrenia (SZ), but controlled comparisons are lacking. Aims A single-blind randomised controlled trial was designed to evaluate whether yoga training or physical exercise training enhance cognitive functions in SZ, based on a prior pilot study. METHODS: Consenting, clinically stable, adult outpatients with SZ (n=286) completed baseline assessments and were randomised to treatment as usual (TAU), supervised yoga training with TAU (YT) or supervised physical exercise training with TAU (PE). Based on the pilot study, the primary outcome measure was speed index for the cognitive domain of 'attention' in the Penn computerised neurocognitive battery. Using mixed models and contrasts, cognitive functions at baseline, 21 days (end of training), 3 and 6 months post-training were evaluated with intention-to-treat paradigm. RESULTS: Speed index of attention domain in the YT group showed greater improvement than PE at 6 months follow-up (p<0.036, effect size 0.51). In the PE group, 'accuracy index of attention domain showed greater improvement than TAU alone at 6-month follow-up (p<0.025, effect size 0.61). For several other cognitive domains, significant improvements were observed with YT or PE compared with TAU alone (p<0.05, effect sizes 0.30-1.97). CONCLUSIONS: Both YT and PE improved attention and additional cognitive domains well past the training period, supporting our prior reported beneficial effect of YT on speed index of attention domain. As adjuncts, YT or PE can benefit individuals with SZ.

Validation of mismatch negativity and P3a for use in multi-site studies of schizophrenia: characterization of demographic, clinical, cognitive, and functional correlates in COGS-2.

Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n=824, SZ n=966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d=0.96) and P3a (d=0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

Protocol to evaluate the impact of yoga supplementation on cognitive function in schizophrenia: a randomised controlled trial.

BACKGROUND: Schizophrenia (SZ) is a chronic illness that is treated symptomatically. Cognitive dysfunction is a core feature of SZ that is relatively intractable to pharmacotherapy. Yoga can improve cognitive function among healthy individuals. A recent open trial indicated significant benefits of yoga training (YT) in conjunction with conventional pharmacotherapy among patients with SZ. AIMS: To describe the protocol for an ongoing randomised controlled trial designed to test whether the reported beneficial effects of YT on cognitive function among SZ patients can be replicated. Secondarily, the effects of YT on daily functioning living skills are evaluated. METHODS: Consenting patients with SZ receive routine clinical treatment and are randomised to adjunctive YT, adjunctive physical exercise (PE) or treatment as usual (proposed N = 234 total, N = 78 in each group). The trial involves YT or PE 5 days a week and lasts 3 weeks. Participants are evaluated thrice over 6 months. Cognitive functions measured by Trail Making Test, University of Pennsylvania Neurocognitive Computerised Battery were primary outcome measures while clinical severity and daily functioning measured by Independent Living Skills Survey were secondary outcome measures. RESULTS: A total of 309 participants have been randomised as of 31 August 2013, which exceeded beyond 294 proposed after attrition. Once participants begin YT or PE they generally complete the protocol. No injuries have been reported. CONCLUSIONS: Short term YT is feasible and acceptable to Indian SZ patients. If beneficial effects of YT are detected, it will provide a novel adjunctive cognitive remediation strategy for SZ patients.

Comparison of auditory and visual oddball fMRI in schizophrenia.

Individuals with schizophrenia often suffer from attentional deficits, both in focusing on task-relevant targets and in inhibiting responses to distractors. Schizophrenia also has a differential impact on attention depending on modality: auditory or visual. However, it remains unclear how abnormal activation of attentional circuitry differs between auditory and visual modalities, as these two modalities have not been directly compared in the same individuals with schizophrenia. We utilized event-related functional magnetic resonance imaging (fMRI) to compare patterns of brain activation during an auditory and visual oddball task in order to identify modality-specific attentional impairment. Healthy controls (n=22) and patients with schizophrenia (n=20) completed auditory and visual oddball tasks in separate sessions. For responses to targets, the auditory modality yielded greater activation than the visual modality (A-V) in auditory cortex, insula, and parietal operculum, but visual activation was greater than auditory (V-A) in visual cortex. For responses to novels, A-V differences were found in auditory cortex, insula, and supramarginal gyrus; and V-A differences in the visual cortex, inferior temporal gyrus, and superior parietal lobule. Group differences in modality-specific activation were found only for novel stimuli; controls showed larger A-V differences than patients in prefrontal cortex and the putamen. Furthermore, for patients, greater severity of negative symptoms was associated with greater divergence of A-V novel activation in the visual cortex. Our results demonstrate that patients have more pronounced activation abnormalities in auditory compared to visual attention, and link modality specific abnormalities to negative symptom severity.

Deficient prepulse inhibition in schizophrenia detected by the multi-site COGS.

BACKGROUND: Startle inhibition by weak prepulses (PPI) is studied to understand the biology of information processing in schizophrenia patients and healthy comparison subjects (HCS). The Consortium on the Genetics of Schizophrenia (COGS) identified associations between PPI and single nucleotide polymorphisms in schizophrenia probands and unaffected relatives, and linkage analyses extended evidence for the genetics of PPI deficits in schizophrenia in the COGS-1 family study. These findings are being extended in a 5-site "COGS-2" study of 1800 patients and 1200 unrelated HCS to facilitate genetic analyses. We describe a planned interim analysis of COGS-2 PPI data. METHODS: Eyeblink startle was measured in carefully screened HCS and schizophrenia patients (n=1402). Planned analyses of PPI (60 ms intervals) assessed effects of diagnosis, sex and test site, PPI-modifying effects of medications and smoking, and relationships between PPI and neurocognitive measures. RESULTS: 884 subjects met strict inclusion criteria. ANOVA of PPI revealed significant effects of diagnosis (p=0.0005) and sex (p<0.002), and a significant diagnosis×test site interaction. HCS>schizophrenia PPI differences were greatest among patients not taking 2nd generation antipsychotics, and were independent of smoking status. Modest but significant relationships were detected between PPI and performance in specific neurocognitive measures. DISCUSSION: The COGS-2 multi-site study detects schizophrenia-related PPI deficits reported in single-site studies, including patterns related to diagnosis, prepulse interval, sex, medication and other neurocognitive measures. Site differences were detected and explored. The target COGS-2 schizophrenia "endophenotype" of reduced PPI should prove valuable for identifying and confirming schizophrenia risk genes in future analyses.

Hyperactivation balances sensory processing deficits during mood induction in schizophrenia.

While impairments in emotion recognition are consistently reported in schizophrenia, there is some debate on the experience of emotion. Only few studies investigated neural correlates of emotional experience in schizophrenia. The present functional magnetic resonance imaging study compared a standard visual mood induction paradigm with an audiovisual method aimed at eliciting emotions more automatically. To investigate the interplay of sensory, cognitive and emotional mechanisms during emotion experience, we examined connectivity patterns between brain areas. Sixteen schizophrenia patients and sixteen healthy subjects participated in two different mood inductions (visual and audiovisual) that were administered for different emotions (happiness, sadness and neutral). Confirming the dissociation of behavioral and neural correlates of emotion experience, patients rated their mood similarly to healthy subjects but showed differences in neural activations. Sensory brain areas were activated less, increased activity emerged in higher cortical areas, particularly during audiovisual stimulation. Connectivity was increased between primary and secondary sensory processing areas in schizophrenia. These findings support the hypothesis of a deficit in filtering and processing sensory information alongside increased higher-order cognitive effort compensating for perception deficits in the affective domain. This may suffice to recover emotion experience in ratings of clinically stable patients but may fail during acute psychosis.

The Healthy Brains and Behavior Study: objectives, design, recruitment, and population coverage.

Violence is increasingly viewed as a public health issue that may be ameliorated by health-based interventions. The Healthy Brains and Behavior Study (HBBS) aims to identify environmental and biological risk factors for aggression in late childhood and to reduce aggression through psychological and nutritional treatments. Utilizing a cross-disciplinary collaborative research approach, the HBBS has both human and animal components. The human component has two stages consisting of risk assessment followed by treatment. The risk assessment is based on 451 community-residing children aged 11-12 years and their caregivers, during which genetic, brain imaging, neuroendocrine, psychophysiology, environment toxicology, neurocognitive, nutrition, psychological, social and demographic risk variables are collected. Children who met criteria (N = 219) for problematic aggressive behaviors were assigned to one of four treatment groups: cognitive-behavior therapy (CBT) alone, nutritional supplements alone, both CBT and nutrition, or treatment-as-usual. Treatment duration was 12 weeks and all children whether in treatment or not were followed-up at three, six, and 12 months. The animal component assessed the effects of dietary omega-3 fatty acids on the development of aggression. This study contributes knowledge on how biological factors interact with social factors in shaping proactive and reactive aggression and assesses the efficacy of treatment approaches to reduce childhood aggression.

Adjunctive cognitive remediation for schizophrenia using yoga: an open, non-randomized trial.

BACKGROUND: Yoga therapy (YT) improves cognitive function in healthy individuals, but its impact on cognitive function among persons with schizophrenia (SZ) has not been investigated. AIMS: Evaluate adjunctive YT for cognitive domains impaired in SZ. METHODS: Patients with SZ received YT or treatment as usual (TAU; n = 65, n = 23, respectively). Accuracy and speed for seven cognitive domains were assessed using a computerized neurocognitive battery (CNB), thus minimizing observer bias. Separately, YT was evaluated among patients with Bipolar I disorder (n = 40), Major Depressive Disorder (n = 37), and cardiology outpatients (n = 68). All patients also received routine pharmacotherapy. Patients were not randomized to YT or TAU. RESULTS: Compared with the SZ/TAU group, the SZ/YT group showed significantly greater improvement with regard to measures of attention following corrections for multiple comparisons; the changes were more prominent among the men. In the other diagnostic groups, differing patterns of improvements were noted with small to medium effect sizes. CONCLUSIONS: Our initial analyses suggest nominally significant improvement in cognitive function in schizophrenia with adjunctive therapies such as YT. The magnitude of the change varies by cognitive domain and may also vary by diagnostic group.

Not pitch perfect: sensory contributions to affective communication impairment in schizophrenia.

BACKGROUND: Schizophrenia patients have vocal affect (prosody) deficits that are treatment resistant and associated with negative symptoms and poor outcome. The neural correlates of this dysfunction are unclear. Prior study has suggested that schizophrenia vocal affect perception deficits stem from an inability to use acoustic cues, notably pitch, in decoding emotion. METHODS: Functional magnetic resonance imaging was performed in 24 schizophrenia patients and 28 healthy control subjects, during the performance of a four-choice (happiness, fear, anger, neutral) vocal affect identification task in which items for each emotion varied parametrically in affective salient acoustic cue levels. RESULTS: We observed that parametric increases in cue levels in schizophrenia failed to produce the same identification rate increases as in control subjects. These deficits correlated with diminished reciprocal activation changes in superior temporal and inferior frontal gyri and reduced temporo-frontal connectivity. Task activation also correlated with independent measures of pitch perception and negative symptom severity. CONCLUSIONS: These findings illustrate the interplay between sensory and higher-order cognitive dysfunction in schizophrenia. Sensory contributions to vocal affect deficits also suggest that this neurobehavioral marker could be targeted by pharmacological or behavioral remediation of acoustic feature discrimination.

Cognitive versus automatic mechanisms of mood induction differentially activate left and right amygdala.

The amygdala plays a key role in emotional processing. The specific contribution of the amygdala during the experience of one's own emotion, however, remains controversial and requires clarification. There is a long-standing debate on hemispheric lateralization of emotional processes, yet few studies to date directly investigated differential activation patterns for the left and right amygdala. Limited evidence supports right amygdala involvement in automatic processes of emotion and left amygdala involvement in conscious and cognitively controlled emotion processing. The present study investigated differential contributions of the left and right amygdala to cognitive and automatic mechanisms of mood induction. Using functional magnetic resonance imaging (fMRI), we examined hemispheric amygdala responses during two mood induction paradigms: a purely visual method presenting face stimuli and an audiovisual method using faces and music. Amygdala responses in 30 subjects (16 females) showed differences in lateralization patterns depending on the processing mode. The left amygdala exhibited comparable activation levels for both methods. The right amygdala, in contrast, showed increased activity only for the audiovisual condition and this activity was increasing over time. The left amygdala showed augmented activity with higher intensity ratings of negative emotional valence. These results support a left-lateralized cognitive and intentional control of mood and a right-sided more automatic induction of emotion that relies less on explicit reflection processes. The modulation of the left amygdala responses by subjective experience may reflect individual differences in the cognitive effort used to induce the mood. Thus, the central role of the amygdala may not be restricted to the perception of emotion in others but also extend into processes involved in regulation of mood.

Abnormal auditory N100 amplitude: a heritable endophenotype in first-degree relatives of schizophrenia probands.

BACKGROUND: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes. METHODS: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity. RESULTS: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio. CONCLUSIONS: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

Amygdala activation at 3T in response to human and avatar facial expressions of emotions.

Facial expressions of emotions are important in nonverbal communication. Although numerous neural structures have been identified to be involved in emotional face processing, the amygdala is thought to be a core moderator. While previous studies have relied on facial images of humans, the present study is concerned with the effect of computer-generated (avatar) emotional faces on amygdala activation. Moreover, elicited activation patterns in response to viewing avatar faces are compared with the neuronal responses to human facial expressions of emotions. Twelve healthy subjects (five females) performed facial emotion recognition tasks with optimized 3T event-related fMRI. Robust amygdala activation was apparent in response to both human and avatar emotional faces, but the response was significantly stronger to human faces in face-sensitive structures, i.e. fusiform gyri. We suggest that avatars could be a useful tool in neuroimaging studies of facial expression processing because they elicit amygdala activation similarly to human faces, yet have the advantage of being highly manipulable and fully controllable. However, the finding of differences between human and avatar faces in face-sensitive regions indicates the presence of mechanisms by which human brains can differentiate between them. This mechanism merits further investigation.

Levels-of-processing effect on frontotemporal function in schizophrenia during word encoding and recognition.

OBJECTIVE: Patients with schizophrenia improve episodic memory accuracy when given organizational strategies through levels-of-processing paradigms. This study tested if improvement is accompanied by normalized frontotemporal function. METHOD: Event-related blood-oxygen-level-dependent functional magnetic resonance imaging (fMRI) was used to measure activation during shallow (perceptual) and deep (semantic) word encoding and recognition in 14 patients with schizophrenia and 14 healthy comparison subjects. RESULTS: Despite slower and less accurate overall word classification, the patients showed normal levels-of-processing effects, with faster and more accurate recognition of deeply processed words. These effects were accompanied by left ventrolateral prefrontal activation during encoding in both groups, although the thalamus, hippocampus, and lingual gyrus were overactivated in the patients. During word recognition, the patients showed overactivation in the left frontal pole and had a less robust right prefrontal response. CONCLUSIONS: Evidence of normal levels-of-processing effects and left prefrontal activation suggests that patients with schizophrenia can form and maintain semantic representations when they are provided with organizational cues and can improve their word encoding and retrieval. Areas of overactivation suggest residual inefficiencies. Nevertheless, the effect of teaching organizational strategies on episodic memory and brain function is a worthwhile topic for future interventional studies.