Hypoactivation of the language network during auditory imagery contributes to hallucinations in Schizophrenia.

Auditory verbal hallucinations (AVHs) involve perceptions, often voices, in the absence of external stimuli, and rank among the most common symptoms of schizophrenia. Metrical stress evaluation requires determination of the stronger syllable in words, and therefore requires auditory imagery, of interest for investigation of hallucinations in schizophrenia. The current functional magnetic resonance imaging study provides an updated whole-brain network analysis of a previously published study on metrical stress, which showed reduced directed connections between Broca's and Wernicke's regions of interest (ROIs) for hallucinations. Three functional brain networks were extracted, with the language network (LN) showing an earlier and shallower blood-oxygen-level dependent (BOLD) response for hallucinating patients, in the auditory imagery condition only (the reduced activation for hallucinations observed in the original ROI-based results were not specific to the imagery condition). This suggests that hypoactivation of the LN during internal auditory imagery may contribute to the propensity to hallucinate. This accords with cognitive accounts holding that an impaired balance between internal and external linguistic processes (underactivity in networks involved in internal auditory imagery and overactivity in networks involved in speech perception) contributes to our understanding of the biological underpinnings of hallucinations.

Reduced Functional Connectivity in Brain Networks Underlying Paired Associates Memory Encoding in Schizophrenia.

BACKGROUND: Deficits in relational episodic memory encoding are characteristic of schizophrenia (SZ), but whole-brain multivariate analyses of these deficits have been lacking. Open science has provided task-based functional magnetic resonance imaging (fMRI) data investigating paired associate encoding in SZ, but it has not yet been mobilized to address this gap in the literature. Therefore, in this study, we use previously unpublished task fMRI data to conduct the first network-level investigation of impaired relational episodic encoding in SZ. METHODS: Using fMRI data acquired from 40 healthy control participants and 40 age- and sex-matched persons with SZ, we examined the networks involved in successful versus unsuccessful encoding of verbal paired associates using an associative semantic strategy. RESULTS: Constrained principal component analysis for fMRI revealed 3 distinct functional networks recruited during encoding: a responding network, a linguistic processing/attention network, and the default mode network. Relative to the healthy control group, the SZ group exhibited aberrant activity in all 3 networks during successful encoding; namely, hypoactivation in the linguistic processing/attention network, lower peak activation in the responding network, and weaker suppression in the default mode network. Independent of group effects, a pattern of stronger anticorrelating linguistic processing/attention-default mode network activity during successful encoding significantly predicted subsequent retrieval of paired associates. CONCLUSIONS: Together with previous observations of language network hypoactivation during controlled semantic processes, these results suggest that abnormalities in networks representing language and meaning may contribute to difficulties employing deep semantic strategies during relational episodic encoding in SZ.

Altered activity in functional brain networks involved in lexical decision making in bipolar disorder: An fMRI case-control study.

BACKGROUND: Brain networks involved in language, attentional and response processes are detectable by fMRI during lexical decision (LD). Here, we investigated possible abnormalities in the functional networks involved in LD in patients with bipolar disorder (BD). METHODS: fMRI and behavioural data were compared between BD (n = 25) and control (n = 21), with groups matched for age and sex. The functional brain networks involved in LD were extracted by manipulating the "word-likeness" of LD stimuli and using a multidimensional analysis method. RESULTS: Attentional, response and language processes were captured in separate function-specific brain networks (default mode network, response network, linguistic processing network, respectively) in the BD and control groups, replicating the results of our previous study in an independent group of healthy adults. Behaviourally, the BD group showed higher performance than the control group in the LD task. Activity in the default mode network (DMN) and the linguistic processing network (LPN) did not differ between the groups, but the BD group had higher activation than the control group in the response network (RESP). LIMITATIONS: Due to the small sample, the study is underpowered, capable of only detecting large effects. CONCLUSIONS: The results suggest that BD may be associated with sustained activity in the RESP network, which might contribute to psychomotor dysfunction in BD. Future studies should investigate the possible link between altered RESP activation and psychomotor disturbances in BD, as well as the basis for altered RESP activity in BD.

Functional brain networks underlying probabilistic reasoning and delusions in schizophrenia.

Delusions in schizophrenia are false beliefs that are assigned certainty and not afforded the scrutiny that normally gives rise to doubt, even under conditions of weak evidence. The goal of the current functional magnetic resonance imaging (fMRI) study is to identify the brain network(s) involved in gathering information under conditions of weak evidence, in people with schizophrenia experiencing delusions. fMRI activity during probabilistic reasoning in people with schizophrenia experiencing delusions (n = 29) compared to people with schizophrenia not experiencing delusions (n = 41) and healthy controls (n = 41) was observed when participants made judgments based on evidence that weakly or strongly matched (or mismatched) with the focal hypothesis. A brain network involved in visual attention was strongly elicited for conditions of weak evidence for healthy controls and patients not experiencing delusions, but this increase was absent for patients experiencing delusions. This suggests that the state associated with delusions manifests in fMRI as reduced activity in an early visual attentional process whereby weak evidence is incorrectly stamped as conclusive, manifestating as a feeling of fluency and misplaced certainty, short-circuiting the search for evidence, and providing a candidate neural process for 'seeding' delusions.

Item-specific overlap between hallucinatory experiences and cognition in the general population: A three-step multivariate analysis of international multi-site data.

Hallucinatory experiences (HEs) can be pronounced in psychosis, but similar experiences also occur in nonclinical populations. Cognitive mechanisms hypothesized to underpin HEs include dysfunctional source monitoring, heightened signal detection, and impaired attentional processes. Using data from an international multisite study on non-clinical participants (N = 419), we described the overlap between two sets of variables - one measuring cognition and the other HEs - at the level of individual items. We used a three-step method to extract and examine item-specific signal, which is typically obscured when summary scores are analyzed using traditional methodologies. The three-step method involved: (1) constraining variance in cognition variables to that which is predictable from HE variables, followed by dimension reduction, (2) determining reliable HE items using split-halves and permutation tests, and (3) selecting cognition items for interpretation using a leave-one-out procedure followed by repetition of Steps 1 and 2. The results showed that the overlap between HEs and cognition variables can be conceptualized as bi-dimensional, with two distinct mechanisms emerging as candidates for separate pathways to the development of HEs: HEs involving perceptual distortions on one hand (including voices), underpinned by a low threshold for signal detection in cognition, and HEs involving sensory overload on the other hand, underpinned by reduced laterality in cognition. We propose that these two dimensions of HEs involving distortions/liberal signal detection, and sensation overload/reduced laterality may map onto psychosis-spectrum and dissociation-spectrum anomalous experiences, respectively.

"Individual Placement and Support" boosts employment for early psychosis clients, even when baseline rates are high.

AIM: Individual Placement and Support is an effective vocational intervention for increasing competitive employment for people with severe mental illness. Little is known, however, about its effectiveness in the context of early psychosis. This study assesses improvements in clients' employment in a phase of illness during which functional abilities often decline. METHODS: The trial design is an assessor-blinded randomized clinical trial, set in the context of a population-based Early Psychosis Intervention program in British Columbia, Canada. Participants were randomized either to 1 year of employment support added to treatment-as-usual, or the latter alone. Interviews at intake captured data regarding demographics, symptom severity, and employment; assessments at 6 and 12 months repeated queries about employment activities. RESULTS: A total of 109 clients were recruited. Employment rates in the Individual Placement and Support group increased over time, unlike the control group. Further, the number of days worked over the 12-month intervention period, compared to the 6 months prior to the study, improved for both groups, but the increase was greater among clients receiving IPS. Sensitivity analysis indicated the advantage in days worked was evident in the second half of the intervention period (6-12 months), but not the first half. CONCLUSIONS: Employment rates, for younger clients in both early-psychosis groups, were high compared to older clients in later stages of illness. In this study, use of the Individual Placement and Support strategy further increased employment, despite the high baseline rates. Further research is needed to identify the optimal timing of employment support for these clients.

Hallucination-Specific structure-function associations in schizophrenia.

Combining structural (sMRI) and functional magnetic resonance imaging (fMRI) data in schizophrenia patients with and without auditory hallucinations (9 SZ_AVH, 12 SZ_nAVH), 18 patients with bipolar disorder, and 22 healthy controls, we examined whether cortical thinning was associated with abnormal activity in functional brain networks associated with auditory hallucinations. Language-task fMRI data were combined with mean cortical thickness values from 148 brain regions in a constrained principal component analysis (CPCA) to identify brain structure-function associations predictable from group differences. Two components emerged from the multimodal analysis. The "AVH component" highlighted an association of frontotemporal and cingulate thinning with altered brain activity characteristic of hallucinations among patients with AVH. In contrast, the "Bipolar component" distinguished bipolar patients from healthy controls and linked increased activity in the language network with cortical thinning in the left occipital-temporal lobe. Our findings add to a body of evidence of the biological underpinnings of hallucinations and illustrate a method for multimodal data analysis of structure-function associations in psychiatric illness.

Premarin has opposing effects on spatial learning, neural activation, and serum cytokine levels in middle-aged female rats depending on reproductive history.

Menopause is associated with cognitive decline, and hormone therapies (HTs) may improve cognition depending on type and timing of HTs. Previous parity may influence cognition in later life. We investigated how primiparity and long-term ovariectomy influence cognition, neurogenesis, hormones, cytokines, and neuronal activation in middle-aged rats in response to Premarin, an HT. Nulliparous and primiparous rats were sham-ovariectomized or ovariectomized, administered vehicle or Premarin 6 months later, and all rats were trained in the Morris water maze. Premarin improved early spatial learning and memory in nulliparous rats but impaired early learning in primiparous rats. With training, primiparity increased hippocampal neurogenesis, and Premarin decreased immature neurons, regardless of parity. Moreover, Premarin increased serum tumor necrosis factor α and the CXC chemokine ligand 1 (CXCL1) in trained nulliparous, but not primiparous, rats. However, Premarin decreased the expression of the immediate early gene zif268 in the dorsal CA3 region in primiparous rats after training. Thus, primiparity alters how Premarin affects spatial learning, neuronal activation, and serum cytokines. These findings have implications for the treatment of age-associated cognitive decline in women.

Sex Hormones and Cognition: Neuroendocrine Influences on Memory and Learning.

Sex differences in neurological disease exist in incidence, severity, progression, and symptoms and may ultimately influence treatment. Cognitive disturbances are frequent in neuropsychiatric disease with men showing greater cognitive impairment in schizophrenia, but women showing more severe dementia and cognitive decline with Alzheimer's disease. Although there are no overall differences in intelligence between the sexes, men, and women demonstrate slight but consistent differences in a number of cognitive domains. These include a male advantage, on average, in some types of spatial abilities and a female advantage on some measures of verbal fluency and memory. Sex differences in traits or behaviors generally indicate the involvement of sex hormones, such as androgens and estrogens. We review the literature on whether adult levels of testosterone and estradiol influence spatial ability in both males and females from rodent models to humans. We also include information on estrogens and their ability to modulate verbal memory in men and women. Estrone and progestins are common components of hormone therapies, and we also review the existing literature concerning their effects on cognition. We also review the sex differences in the hippocampus and prefrontal cortex as they relate to cognitive performance in both rodents and humans. There has been greater recognition in the scientific literature that it is important to study both sexes and also to analyze study findings with sex as a variable. Only by examining these sex differences can we progress to finding treatments that will improve the cognitive health of both men and women. © 2016 American Physiological Society. Compr Physiol 6:1295-1337, 2016.

Theory of mind in social anxiety disorder, depression, and comorbid conditions.

Social anxiety disorder is characterized by marked interpersonal impairment, particularly when presenting with comorbid major depression. However, the foundational social-cognitive skills that underlie interpersonal impairment in comorbid and non-comorbid manifestations of SAD has to date received very little empirical investigation. In a sample of 119 young adults, the current study examined differences in theory of mind (ToM), defined as the ability to decode and reason about others' mental states, across four groups: (a) non-comorbid SAD; (b) non-comorbid Lifetime MDD; (c) comorbid SAD and Lifetime MDD; and (d) healthy control. The non-comorbid SAD group was significantly less accurate at decoding mental states than the non-comorbid MDD and control groups. Further, both the comorbid and non-comorbid SAD groups made significantly more 'excessive' ToM reasoning errors than the non-comorbid MDD group, suggesting a pattern of over-mentalizing. Findings are discussed in terms of their implications for understanding the social cognitive foundations of social anxiety.