Neuroanatomical profiles of treatment-resistance in patients with schizophrenia spectrum disorders.

Widespread structrual abnormalities in subcortical brain regions have been identified in patients with schizophrenia. However, only a few studies have examined the neuroanatomical profiles of patients with treatment-resistant schizophrenia. The aim of this study was to compare differences in subcortical and hippocampal volumes between: (i) treatment-resistant patients who are non-responders to both first-line antipsychotics and clozapine (URS), (ii) treatment-resistant patients who are non-responders to first-line antipsychotics but are responders to clozapine (CLZ-Resp), (iii) responders to first-line antipsychotics (FL-Resp), and (iv) healthy controls. T1-weighted images of 103 participants (27 URS, 29 CLZ-Resp, 21 FL-Resp, and 26 healthy controls) were obtained. Group differences in striatal, thalamic, globus pallidus, amygdala, and hippocampus volumes were examined. Multiple regression analyses were performed to examine the associations between subcortical and hippocampal volumes and participant characteristics. The FL-Resp group showed larger striatal and globus pallidus volumes compared to the URS group and larger post-commissural putamen and globus pallidus volumes compared to healthy controls. The URS group showed smaller thalamic volume compared to healthy controls. There were no subcortical or hippocampal volume differences between the URS and CLZ-Resp groups. Differences in subcortical and hippocampal structural volumes were not related to symptom severity or chlorpromazine antipsychotic dose equivalents. Our findings suggest different structural volume alterations in subcortical brain regions between treatment-resistant schizophrenia and responders to first-line antipsychotics. Whether subcortical structure compromise is a distinct pathophysiological marker of treatment-resistant schizophrenia, or a result of antipsychotic exposure, remains to be explored.

Modulation of brain activity with transcranial direct current stimulation: Targeting regions implicated in impaired illness awareness in schizophrenia.

BACKGROUND: Impaired illness awareness or insight into illness (IIA) is a common feature of schizophrenia that contributes to medication nonadherence and poor clinical outcomes. Neuroimaging studies suggest IIA may arise from interhemispheric imbalance in frontoparietal regions, particularly in the posterior parietal area (PPA) and the dorsolateral prefrontal cortex (dlPFC). In this pilot study, we examined the effects of transcranial direct current stimulation (tDCS) on brain regions implicated in IIA. METHODS: Eleven patients with schizophrenia with IIA (≥3 PANSS G12) and 10 healthy controls were included. A crossover design was employed where all participants received single-session bi-frontal, bi-parietal, and sham stimulation in random order. For each condition, we measured (i) blood oxygen level-dependent (BOLD) response to an illness awareness task pre- and post-stimulation, (ii) regional cerebral blood-flow (rCBF) prior to and during stimulation, and (iii) changes in illness awareness. RESULTS: At baseline, patients with schizophrenia showed higher BOLD-response to an illness awareness task in the left-PPA compared to healthy controls. Bi-parietal stimulation reduced the interhemispheric imbalance in the PPA compared to sham stimulation. Relatedly, bi-parietal stimulation increased rCBF beneath the anode (21% increase in the right-PPA), but not beneath the cathode (5.6% increase in the left-PPA). Bi-frontal stimulation did not induce changes in rCBF. We found no changes in illness awareness. CONCLUSION: Although single-session tDCS did not improve illness awareness, this pilot study provides mechanistic justification for future investigations to determine if multi-session bi-parietal tDCS can induce sustained changes in brain activity in the PPA in association with improved illness awareness.

Acute and long-term effects of electroconvulsive therapy on human dentate gyrus.

Electroconvulsive therapy (ECT) is the most effective treatment for severe depression, although the underlying mechanisms remain unclear. Animal studies have consistently shown that electroconvulsive stimulation induces neuroplastic changes in the dentate gyrus. To date, few studies have investigated the effect of ECT on human hippocampal subfields. In the current study, structural magnetic resonance imaging (MRI) was conducted in 25 patients with major depressive episodes at 3 time points: before ECT (TP1), after 1 week of the last ECT (TP2) and after 3 months of the last ECT (TP3). Twenty healthy controls were scanned twice with an interval similar to patients between TP1 and TP2. Volumetric analyses of the cornu ammonis (CA)4/dentate gyrus (DG) were performed using the MAGeT-Brain (Multiple Automatically Generated Templates) algorithm. Clinically remitted patients after ECT showed larger volume increases in the right CA4/DG than non-remitted patients. Volume increases in the right CA4/DG were negatively associated with age. Increased CA4/DG volumes after ECT returned to baseline levels after 3 months irrespective of clinical state. ECT-induced volume increase in the CA4/DG was associated with age and clinical remission. These findings are consistent with the neurotrophic processes seen in preclinical studies. Neuroplastic change in the CA4/DG might mediate some of the short-term antidepressant effects of ECT.

A meta-analysis of transcranial direct current stimulation for schizophrenia: "Is more better?"

Transcranial direct current stimulation (tDCS) has generated interest in recent years as a potential adjunctive treatment for patients with schizophrenia. The primary objective of this meta-analysis was to evaluate the efficacy of tDCS on positive symptoms, particularly auditory hallucinations, and negative symptoms. A literature search of randomized sham-controlled trials was conducted using the OVID database on October 9, 2018. The standardized mean differences (SMDs) were calculated to examine changes in symptom severity between active and sham groups for the following symptom domains: auditory hallucinations, positive symptoms (including auditory hallucinations), and negative symptoms. Moderator analyses were performed to examine the effects of study design and participant demographics. We identified 10 eligible studies. Main-analyses showed no effects of tDCS on auditory hallucinations (7 studies, n = 242), positive symptoms (9 studies, n = 313), or negative symptoms (9 studies, n = 313). Subgroup analyses of studies that applied twice-daily stimulation showed a significant reduction in the severity of auditory hallucinations (4 studies, n = 138, SMD = 1.04, p = 0.02). Studies that applied ≥10 stimulation sessions showed a reduction in both auditory hallucination (5 studies, n = 186, SMD = 0.86, p = 0.009) and negative symptom severity (7 studies, n = 257, SMD = 0.41, p = 0.04). Meta-regression analyses revealed a negative association between mean age and the SMDs for auditory hallucinations and negative symptoms, and a positive association between baseline negative symptom severity and the SMDs for negative symptoms. Our findings highlight the need to optimize tDCS parameters and suggest twice-daily or 10 or more stimulation sessions may be needed to improve clinical outcomes in patients with schizophrenia.

The effects of illness severity, cognition, and estimated antipsychotic dopamine receptor occupancy on insight into the illness in schizophrenia: An analysis of clinical antipsychotic trials of intervention effectiveness (CATIE) data.

BACKGROUND: The relationship between dopamine D2 receptor (D2R) occupancy and impaired illness awareness (IIA) remains unclear. While IIA is associated with illness severity and cognitive dysfunction, antipsychotic medication, the principal treatment for schizophrenia, indirectly improves IIA, but may simultaneously contribute to cognitive dysfunction at supratherapeutic doses. AIM AND METHODS: We investigated the influence of estimated D2R (Est.D2R) occupancy by antipsychotics on the relationships between IIA and illness severity, and IIA and cognition. IIA was assessed in 373 adult patients with schizophrenia (18-62 years) using data from CATIE. IIA was measured using the Positive and Negative Syndrome Scale (PANSS) item G12. D2R occupancy levels were estimated from plasma concentrations for risperidone, olanzapine, and ziprasidone. Correlation, regression, and path analyses were performed to examine IIA's relationship to illness severity, cognition, and Est.D2R. RESULTS: Illness severity was predictive of IIA. However, premorbid IQ, cognition, and Est.D2R did not predict IIA, and Est.D2R did not serve either a moderating or mediating role in both regression and path analyses. CONCLUSIONS: Consistent with previous literature, our results suggest that IIA is a function of illness severity in adult patients with schizophrenia. Future studies should explore whether D2R occupancy mediates the relationships between IIA and illness severity, and IIA and cognitive dysfunction, in late-life schizophrenia (i.e. ≥60 years) given the effects of aging on cognition, IIA, and antipsychotic sensitivity.

OASIS: The Obesity Awareness and Insight Scale.

AIMS: Impaired illness awareness or not accepting that one has obesity is an understudied phenomenon that may negatively influence treatment adherence and clinical outcomes. The purpose of this study was to perform a systematic review of available measures of obesity awareness, and subsequently develop and validate a novel scale that measures the core domains of obesity awareness. METHODS: A systematic review of the literature revealed no illness specific measure of subjective obesity awareness. As such, we designed the Obesity Awareness and Insight Scale (OASIS) to assess the following core domains of illness awareness: General Illness Awareness,, Symptom Attribution,, Awareness of Need for Treatment and the Negative Consequences attributable to the illness (www.illnessawarenessscales.com). Participants (n=100) were recruited from an online survey platform to assess the psychometric properties of OASIS. RESULTS: The OASIS demonstrated strong internal consistency (Cronbach's alpha=0.89), convergent (r(98)=0.65, p<0.001) and discriminant validity, and test-retest reliability (intra-class correlation=0.76). An exploratory factor analysis of OASIS revealed a single latent component. CONCLUSIONS: OASIS is an obesity-specific instrument that comprehensively measures subjective obesity awareness. OASIS can be used in epidemiological studies, intervention trials and clinical practice to assess the impact of obesity awareness on treatment adherence and outcomes.

Reprint of OASIS - Obesity Awareness and Insight Scale.

AIMS: Impaired illness awareness or not accepting that one has obesity is an understudied phenomenon that may negatively influence treatment adherence and clinical outcomes. The purpose of this study was to perform a systematic review of available measures of obesity awareness, and subsequently develop and validate a novel scale that measures the core domains of obesity awareness. METHODS: A systematic review of the literature revealed no illness specific measure of subjective obesity awareness. As such, we designed the Obesity Awareness and Insight Scale (OASIS) to assess the following core domains of illness awareness: General Illness Awareness, Symptom Attribution, Awareness of Need for Treatment and the Negative Consequences attributable to the illness (www.illnessawarenessscales.com). Participants (n=100) were recruited from an online survey platform to assess the psychometric properties of OASIS. RESULTS: The OASIS demonstrated strong internal consistency (Cronbach's alpha=0.89), convergent (r(98)=0.65, p<0.001) and discriminant validity, and test-retest reliability (intra-class correlation=0.76). An exploratory factor analysis of OASIS revealed a single latent component. CONCLUSIONS: OASIS is an obesity-specific instrument that comprehensively measures subjective obesity awareness. OASIS can be used in epidemiological studies, intervention trials, and clinical practice to assess the impact of obesity awareness on treatment adherence and outcomes.

Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study.

BACKGROUND: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. OBJECTIVE: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-ß deposition, glucose metabolism, and brain volumes in each stage of AD. METHODS: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-ß deposition (n = 825), brain metabolism (n = 1,304), and brain volumes (n = 1,606) among three groups using data for 18F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. RESULTS: Duration of education had no correlations with amyloid-ß deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. CONCLUSIONS: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.

BASIS: The blood pressure awareness and insight scale.

Impaired illness awareness or not accepting that one has hypertension (HTN) may be an important predictor of treatment adherence and optimal blood pressure control. The purpose of this study was to perform a systematic review of available instruments to evaluate HTN awareness, and subsequently present a novel scale that measures the core domains of subjective illness awareness in HTN. Based on the absence of any validated HTN specific measure identified through our review, the Blood Pressure Awareness and Insight Scale (BASIS) was developed (www.illnessawarenessscales.com). An online survey platform was used to collect data on 100 participants. BASIS showed good concurrent (r(98) = .65, P < 0.001) and discriminant validity, internal consistency (Cronbach's α = .75), and 1-month test-retest reliability (ICC = 0.77). BASIS is a comprehensive, easy-to-use instrument specifically designed to measure subjective HTN awareness. BASIS may be used in research studies and clinical practice to assess the impact of HTN awareness on treatment adherence and clinical outcomes.

Neurometabolite levels in antipsychotic-naïve/free patients with schizophrenia: A systematic review and meta-analysis of 1H-MRS studies.

BACKGROUND: Studies using proton magnetic resonance spectroscopy (1H-MRS) have reported altered neurometabolite levels in patients with schizophrenia. However, results are possibly confounded by the influence of antipsychotic (AP). Thus, this meta-analysis aimed to examine neurometabolite levels in AP-naïve/free patients with schizophrenia. METHODS: A literature search was conducted using Embase, Medline, and PsycINFO to identify studies that compared neurometabolite levels in AP-naïve/free patients with schizophrenia to healthy controls (HCs). Eight neurometabolites (glutamate, glutamine, glutamate + glutamine, N-acetylaspartate [NAA], choline, creatine, myo-inositol, and γ-Aminobutyric acid [GABA]) and seven regions of interest (ROI; medial prefrontal cortex, dorsolateral prefrontal cortex, frontal white matter, occipital lobe, basal ganglia, hippocampus/medial temporal lobe, and thalamus) were examined. RESULTS: Twenty-one studies (N = 1281) were included in the analysis. The results showed lower thalamic NAA levels (3 studies, n = 174, effect size = -0.56, P = 0.0005) in the patient group. No group differences were identified for other neurometabolites. CONCLUSIONS: Our findings suggest that impaired neuronal integrity in the thalamus may be a potential trait maker in the early stages of schizophrenia.

Striatal neurometabolite levels in patients with schizophrenia undergoing long-term antipsychotic treatment: A proton magnetic resonance spectroscopy and reliability study.

Previous proton magnetic resonance spectroscopy (1H-MRS) studies have reported disrupted levels of various neurometabolites in patients with schizophrenia. An area of particular interest within this patient population is the striatum, which is highly implicated in the pathophysiology of schizophrenia. The present study examined neurometabolite levels in the striatum of 12 patients with schizophrenia receiving antipsychotic treatment for at least 1 year and 11 healthy controls using 3-Tesla 1H-MRS (PRESS, TE = 35 ms). Glutamate, glutamate+glutamine (Glx), myo-inositol, choline, N-acetylaspartate, and creatine levels were estimated using LCModel, and corrected for fraction of cerebrospinal fluid in the 1H-MRS voxel. Striatal neurometabolite levels were compared between groups. Multiple study visits permitted a reliability assessment for neurometabolite levels (days between paired 1H-MRS acquisitions: average = 90.33; range = 7-306). Striatal neurometabolite levels did not differ between groups. Within the whole sample, intraclass correlation coefficients for glutamate, Glx, myo-inositol, choline, and N-acetylaspartate were fair to excellent (0.576-0.847). The similarity in striatal neurometabolite levels between groups implies a marked difference from the antipsychotic-naïve first-episode state, especially in terms of glutamatergic neurometabolites, and might provide insight regarding illness progression and the influence of antipsychotic medication.

Effect of electroconvulsive therapy on hippocampal and amygdala volumes: systematic review and meta-analysis.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments for depression, although the underlying mechanisms remain unclear. Animal studies have shown that electroconvulsive shock induced neuroplastic changes in the hippocampus. Aims To summarise volumetric magnetic resonance imaging studies investigating the effects of ECT on limbic brain structures. METHOD: A systematic review and meta-analysis was conducted to assess volumetric changes of each side of the hippocampus and amygdala before and after ECT. Standardised mean difference (SMD) was calculated. RESULTS: A total of 8 studies (n = 193) were selected for our analyses. Both right and left hippocampal and amygdala volumes increased after ECT. Meta-regression analyses revealed that age, percentage of those responding and percentage of those in remission were negatively associated with volume increases in the left hippocampus. CONCLUSIONS: ECT increased brain volume in the limbic structures. The clinical relevance of volume increase needs further investigation. Declaration of interest None.

Reduced insulin sensitivity may be related to less striatal glutamate: An 1H-MRS study in healthy non-obese humans.

Levels of striatal dopamine (DA) may be positively correlated with levels of striatal glutamate (Glu). While reduced insulin sensitivity (%S) has been associated with reduced striatal DA levels in healthy non-obese persons, whether reduced %S is also associated with reduced striatal Glu levels has not yet been established. Using 1H-MRS, we measured levels of several neurometabolites in the striatum and dorsolateral prefrontal cortex (DLPFC) of seventeen healthy non-obese persons (9 female, mean age: 28.35 ± 9.53). Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. We hypothesized that %S would be positively related with levels of Glu and Glu + glutamine (Glx) in the striatum. Exploratory analyses were also conducted between other fasting markers of metabolic health and neurometabolites measured with 1H-MRS. In the right striatum, %S was positively correlated with levels of Glu (r(15) = .49, p = .04) and Glx (r(15) = .50, p = .04). In the left striatum, there was a trend positive correlation between %S and Glu (r(15) = .46, p = .06), but not Glx levels (r(15) = .20, p = .44). The relationships between %S and striatal Glu levels remained after controlling for age, sex, and BMI (right: r(12) = .73, ß = .52, t = 2.55, p = .03; left: (r(12) = .63, ß = .53, t = 2.25, p = .04) These preliminary findings suggest that %S may be related to markers of glutamatergic functioning in the striatum of healthy non-obese persons. These findings warrant replication in larger samples and extension into neuropsychiatric populations where altered striatal DA, Glu, and %S are implicated.

Amotivation is associated with smaller ventral striatum volumes in older patients with schizophrenia.

OBJECTIVE: Motivational deficits are prevalent in patients with schizophrenia, persist despite antipsychotic treatment, and predict long-term outcomes. Evidence suggests that patients with greater amotivation have smaller ventral striatum (VS) volumes. We wished to replicate this finding in a sample of older, chronically medicated patients with schizophrenia. Using structural imaging and positron emission tomography, we examined whether amotivation uniquely predicted VS volumes beyond the effects of striatal dopamine D2/3 receptor (D2/3 R) blockade by antipsychotics. METHODS: Data from 41 older schizophrenia patients (mean age: 60.2 ± 6.7; 11 female) were reanalysed from previously published imaging data. We constructed multivariate linear stepwise regression models with VS volumes as the dependent variable and various sociodemographic and clinical variables as the initial predictors: age, gender, total brain volume, and antipsychotic striatal D2/3 R occupancy. Amotivation was included as a subsequent step to determine any unique relationships with VS volumes beyond the contribution of the covariates. In a reduced sample (n = 36), general cognition was also included as a covariate. RESULTS: Amotivation uniquely explained 8% and 6% of the variance in right and left VS volumes, respectively (right: ß = -.38, t = -2.48, P = .01; left: ß = -.31, t = -2.17, P = .03). Considering cognition, amotivation levels uniquely explained 9% of the variance in right VS volumes (ß = -.43, t = -0.26, P = .03). CONCLUSION: We replicate and extend the finding of reduced VS volumes with greater amotivation. We demonstrate this relationship uniquely beyond the potential contributions of striatal D2/3 R blockade by antipsychotics. Elucidating the structural correlates of amotivation in schizophrenia may help develop treatments for this presently irremediable deficit.

Anosognosia Is an Independent Predictor of Conversion From Mild Cognitive Impairment to Alzheimer's Disease and Is Associated With Reduced Brain Metabolism.

OBJECTIVE: Anosognosia, or impaired illness awareness, is a common feature of Alzheimer's disease (AD) and less so of mild cognitive impairment (MCI). Importantly, anosognosia negatively influences clinical outcomes for patients and their caregivers and may predict the conversion from MCI to AD. This study aimed to examine (1) the relationship between brain glucose metabolism as measured by fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and anosognosia in patients with MCI and AD and (2) the predictive utility of anosognosia in patients with MCI for later conversion to AD, even when controlling for other factors, including gender, education, apolipoprotein E ε4 carrier status, dementia severity, and cognitive dysfunction. METHODS: Data for 1,062 participants from the Alzheimer's Disease Neuroimaging Initiative database (2003 to August 2015) classified as having AD (n = 191) or MCI (n = 499) or as healthy comparison (HC) subjects (n = 372) were analyzed. HC participants had Mini-Mental State Examination (MMSE) scores from 24 to 30 and a Clinical Dementia Rating (CDR) of 0. MCI participants had MMSE scores from 24 to 30, a memory complaint, objective memory loss, a CDR of 0.5, absence of significant levels of impairment in other cognitive domains, and essentially preserved activities of daily living. AD participants had MMSE scores ≤ 26 and a CDR of ≥ 0.5, and met National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD. Anosognosia was measured with the composite discrepancy score of the study partner and participants' scores on the Everyday Cognition scale (ECog). Bivariate correlations and multiple regression analyses were performed to assess the relationship between anosognosia and FDG-PET findings in each group. Lastly, logistic regression and receiver operating characteristic curve analyses were performed in the MCI sample to determine if anosognosia was predictive of conversion from MCI to AD. RESULTS: Hypometabolism was independently associated with anosognosia in AD, particularly in the posterior cingulate cortex and right angular gyrus. Anosognosia was associated with conversion from MCI to AD within 5 years (OR = 2.74 [95% CI, 1.95 to 3.85], χ²1 = 33.65, P < .001), even after including covariates (OR = 1.64 [95% CI, 1.12 to 2.40], χ²1 = 6.43, P = .011). ECog-composite scores ≤ -0.75 were 93% sensitive and 15% specific for conversion from MCI to AD. CONCLUSIONS: Anosognosia in AD is related to brain glucose hypometabolism. Further, anosognosia independently predicts conversion from MCI to AD. The absence of anosognosia may be clinically useful to identify those patients that are unlikely to convert from MCI to AD.

Comparison of clinician-rated and self-report insight in Korean patients with schizophrenia using VAGUS insight scale.

This study was aimed to explore self-report auditory verbal hallucinations to provide unique and valuable information in addition to clinician-rated assessment in patients with schizophrenia. The VAGUS (http://www.vagusonline.com) is a recently developed insight scale that includes both clinician-rated (CR) and self-report (SR) versions. Insight measures obtained by the two versions of the VAGUS from the clinicians and the patients, respectively, in forty-one patients diagnosed with schizophrenia by DSM-IV-TR criteria were compared. Correlation coefficients for inter-scale convergence and 3-D biplots for multivariate relationship were derived from the subscales of the VAGUS. For external validation, correlation analyses with abridged version of Scale to Assess Unawareness in Mental Disorder (SUMD-A) and PANSS G12 item were conducted. Total scores of VAGUS-CR and -SR were 5.2 ± 2.6 and 4.9 ± 2.2, respectively. There was a strong correlation between them along with moderate pairwise correlations among the subscales. The 3-D biplots demonstrated that most subscales were clustered as a single factor apart from self-report Symptom Attribution separated as an independent factor. The VAGUS-CR, not -SR correlated significantly with the SUMD-A and PANSS G12. The utility of the VAGUS in reaching more overall understanding of the elusive phenomenon of insight in patients with schizophrenia is discussed.

Trait impulsiveness is related to smaller post-commissural putamen volumes in males but not females.

Impulsivity is considered a vulnerability trait for addiction. Recently, we found trait non-planning impulsiveness measured with the Karolinska Scales of Personality was negatively correlated with dopamine D2/3 receptor availability in the ventral striatum of healthy humans. While also observed in rodents, human studies have failed to find this association with other measures of trait impulsivity. We explored whether another rodent finding, reduced ventral striatum volume with greater impulsivity, could also be observed in humans using this scale. Non-planning impulsiveness was measured in 52 healthy subjects (21 female; mean age: 33.06 ± 9.69) using the Karolinska Scales of Personality. Striatal subregion volumes, including the globus pallidus, were acquired using the Multiple Automatically Generated Templates (MAGeT-Brain) algorithm. Although failing to support our a priori hypothesis, there was a significant sex interaction in the post-commissural putamen with impulsiveness. Exploratory analyses revealed impulsiveness was negatively correlated with post-commissural putamen volumes in males, but positively correlated in females. We replicated this finding in males in an increased sample (including all 52 previous subjects) who provided impulsiveness measured by the Temperament and Character Inventory (n = 73; 32 female; mean age: 33.48 ± 9.75). These correlations by sex were statistically different from one another, the main finding with the Kasolinksa Scales of Personality surviving correction for multiple comparisons. While impulsivity may be related to reduced ventral striatal D2/3 receptors across sexes, males but not females may show significant reductions in post-commissural putamen volume. These findings have important implications for understanding biological markers underlying sex differences in drug addiction vulnerability.

The Effects of Cortical Hypometabolism and Hippocampal Atrophy on Clinical Trajectories in Mild Cognitive Impairment with Suspected Non-Alzheimer's Pathology: A Brief Report.

The clinical and structural trajectories of suspected non-Alzheimer' pathology (SNAP) remain elusive due to its heterogeneous etiology. Baseline and longitudinal clinical (global cognition, daily functioning, symptoms of dementia, and learning memory) and hippocampal volume trajectories over two years were compared between patients with amnestic mild cognitive impairment (aMCI) with SNAP with reduced hippocampal volumes (SNAP+HIPPO) and aMCI patients with SNAP without reduced hippocampal volumes. SNAP+HIPPO showed overall worse baseline cognitive functions. Longitudinally, SNAP+HIPPO showed faster deterioration of clinical symptoms of dementia. Having both hippocampal atrophy and cortical hypometabolism without amyloid pathology may exacerbate symptoms of dementia in aMCI.

Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer's Disease Pathology.

Suspected non-Alzheimer's disease pathology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-ß (Aß). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimer's Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aß+ND+), amyloid only (Aß+ND-), neither amyloid nor hypometabolism (Aß-ND-), and SNAP (Aß-ND+). Aß+ND+(n = 33), Aß+ND-(n = 32), and Aß-ND-(n = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n = 40) were also matched to SNAP for age, gender, and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aß+groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aß-ND-and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aß-ND-and controls. However, Aß+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aß-ND-and controls, 2) no differences with Aß+ND-, and 3) less cognitive deterioration than Aß+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades.

Intranasal oxytocin does not modulate jumping to conclusions in schizophrenia: Potential interactions with caudate volume and baseline social functioning.

BACKGROUND: Patients with schizophrenia (SCZ) tend to sample less information when making a decision, jumping to conclusions (JTC) without sufficient evidence. This "JTC bias" may be a trait marker of the disease and may not improve with antipsychotic treatment. We conducted a double-blind, placebo-controlled trial to test whether intranasal oxytocin could reduce JTC in stable, medicated patients with SCZ and healthy controls (HCs). We also explored whether striatal volume, clinical symptoms, and baseline social functioning (SF) was related to JTC performance. METHODS: Forty-three male, medicated SCZ patients (Mean Age: 40.81±11.44) and sixteen HCs (Mean Age: 30.38±9.85) participated in a double-blind, placebo-controlled, cross-over study. Participants completed the Beads Task on two separate visits (minimum 20days apart). Participants were randomized to receive either intranasal oxytocin (50IU in solution) or intranasal placebo (saline). Twenty of the SCZ patients and all sixteen HCs also provided T1 MRIs (3-T). RESULTS: Patients with SCZ took fewer draws to decision (DTD) than HCs (t(57)=2.78, p=0.007). Oxytocin did not significantly change DTD in patients (t(42)=-1.11, p=0.27), nor in HCs (t(15)=-0.62, p=0.55). Exploratory analyses found ventral caudate volumes were negatively correlated with DTD (r(18)=-0.50, p=0.03) in patients. Moreover, oxytocin was more likely to improve JTC in patients with lower baseline SF. However, these exploratory findings did not survive correction for multiple comparisons. CONCLUSIONS: We replicate increased JTC in SCZ. However, acute intranasal oxytocin did not modify JTC. Future studies with larger samples should explore how brain morphology and SF are related to JTC performance in patients with SCZ.