Impact of family history of alcoholism on glutamine/glutamate ratio in anterior cingulate cortex in substance-naïve adolescents

Neuroimaging studies of individuals with family histories of alcoholism provide evidence suggesting neurobiological risk factors for alcoholism. Youth family history positive (FH+) for alcoholism exhibit increased impulsivity compared to family history negative (FH−) peers in conjunction with altered functional activation in prefrontal cortex, including anterior cingulate cortex (ACC). This study examined glutamate (Glu) and glutamine (Gln), amino acids vital to protein synthesis, cellular metabolism and neurotransmission, acquired from ACC and parieto-occipital cortex (POC) using magnetic resonance spectroscopy (MRS) at 4T. Participants were 28 adolescents (13 male, 12–14 yrs) and 31 emerging adults (16 male, 18–25 yrs), stratified into FH− and FH+ groups. Significantly higher ACC Gln/Glu was observed in emerging adults versus adolescents in FH− but not FH+ groups. In FH− adolescents, higher impulsivity was significantly associated with higher ACC Gln/Glu. In FH+ emerging adults, higher impulsivity was negatively associated with ACC Gln/Glu. No differences or associations were observed for POC. These findings provide preliminary evidence that family history of alcoholism is associated with a neurochemical profile that may influence normative age differences in glutamatergic metabolites and their association with impulse control, which together could confer greater genetic risk of addiction later in life.     

Abnormal functional connectivity of high-frequency rhythms in drug-naïve schizophrenia

Objective

The “dysconnection hypothesis” has been proposed as a core neural basis for schizophrenia. Although growing neuroimaging-based evidence suggests atypical functional connectivity in patients with schizophrenia, the results are inconsistent and the effects of antipsychotic treatment remain elusive.

Parental substance abuse and function of the motivation and behavioral inhibition systems in drug-naïve youth

It is hypothesized that the development of substance abuse (SA) may be due to imbalance in functions of the motivation-reward and behavioral inhibition systems in the brain. This speaks to the search for biological risk factors for SA in drug-na?ve children who also exhibit motivational and inhibitory control deficits; however, this type of research is currently lacking. The objective of this study was to establish a neurobiological basis for addiction vulnerability using functional magnetic resonance imaging (fMRI) in drug-na?ve youth with attention deficit/hyperactivity disorder (ADHD). We hypothesized that children with ADHD alone would show higher activity in regions of the motivation-reward and behavioral inhibition systems than children with ADHD and a parental history of SA. Toward this goal we scanned 20 drug-na?ve children with ADHD ages 8-13 while performing an event-related reward task. High (N=10) and low (N=10) risk subjects were identified, based on parental history of SA. The effects of anticipation, conflict, and reward were assessed with appropriate linear contrasts, and between-group differences were assessed using statistical parametric mapping. The two groups did not differ on behavioral measures of the task. The fMRI results show heightened activation in the brain motivational-reward system and reduced activation of the inhibitory control system in high-risk compared to low-risk children. These results suggest that a functional mismatch between these two systems may represent one possible biological underpinning of SA risk, which is conferred by a parental history of addiction.     

Differential brain glucose metabolic patterns in antipsychotic-naïve first-episode schizophrenia with and without auditory verbal hallucinations

Background

Auditory verbal hallucinations (AVHs) are a core symptom of schizophrenia. Previous reports on neural activity patterns associated with AVHs are inconsistent, arguably owing to the lack of an adequate control group (i.e., patients with similar characteristics but without AVHs) and neglect of the potential confounding effects of medication.

Methods

The current study was conducted in a homogeneous group of patients with schizophrenia to assess whether the presence or absence of AVHs was associated with differential regional cerebral glucose metabolic patterns. We investigated differences between patients with commenting AVHs and patients without AVHs among a group of dextral antipsychotic-naive inpatients with acute first-episode schizophrenia examined with [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) at rest. Univariate and multivariate approaches were used to establish between-group differences.

Results

We included 9 patients with AVHs and 7 patients without AVHs in this study. Patients experiencing AVHs during FDG uptake had significantly higher metabolic rates in the left superior and middle temporal cortices, bilateral superior medial frontal cortex and left caudate nucleus (cluster level p < 0.005, family wise error–corrected, and bootstrap ratio > 3.3, respectively). Additionally, the multivariate method identified hippocampal–parahippocampal, cerebellar and parietal relative hypoactivity during AVHs in both hemispheres (bootstrap ratio < −3.3).

Limitations

The FDG-PET imaging technique does not provide information regarding the temporal course of neural activity. The limited sample size may have increased the risk of false-negative findings.

Conclusion

Our results indicate that AVHs in patients with schizophrenia may be mediated by an alteration of neural pathways responsible for normal language function. Our findings also point to the potential role of the dominant caudate nucleus and the parahippocampal gyri in the pathophysiology of AVHs. We discuss the relevance of phenomenology-based grouping in the study of AVHs.     

Pretreatment and longitudinal studies of neuropsychological deficits in antipsychotic-naïve patients with schizophrenia

The early course of neuropsychological dysfunction in schizophrenia and the impact of treatment on these deficits need to be better specified. A sample of 45 patients with schizophrenia underwent five neuropsychological evaluations from prior to treatment with antipsychotic treatment through a 2-year follow-up period. A comparison sample of 33 matched healthy individuals underwent neuropsychological evaluations at similar time points. At baseline, a generalized deficit across cognitive domains was evident for the schizophrenia sample. After 6 weeks of treatment, patients showed modest improvements in visual memory and visual perception, but a decline in verbal memory. Verbal memory performance returned to baseline levels by the 6-month follow-up while deficits in other neuropsychological domains persisted throughout the 2-year period. Relatively static and generalized neuropsychological dysfunction, evident from illness onset, is consistent with neurodevelopmental rather than neurodegenerative models of schizophrenia.     

Hyper- and hypo-connectivity in sensorimotor network of drug-naïve patients with cervical dystonia

BackgroundCervical dystonia (CD) is the most common form of focal dystonia with involuntary movements and postures of the head. The pathogenesis and neural mechanisms underlying CD have not been fully elucidated.MethodsTwenty-seven newly drug-naïve patients with CD and 21 healthy controls (HCs) were recruited with clinical assessment and resting-state functional magnetic resonance imaging (rs-fMRI) scanning. Severity of CD was measured by Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and Tsui scores. Whole-brain voxel-wise intrinsic connectivity (IC) and seed-based functional connectivity (FC) analyses were performed for detection of changes in the CD group relative to HCs, controlling for age, gender, and global time series correlation, followed by correlation analyses of IC, seed-based FC and clinically relevant features, respectively.ResultsIn comparison with HCs, CD patients showed significantly increased IC measurement in the anterior part of the left supramarginal gyrus and extended to the inferior left postcentral gyrus (AL-SMG/IL-PCG). With this cluster as a seed, decreased FC was found in the right precentral and postcentral gyrus. Moreover, the regional IC value in the AL-SMG/IL-PCG was significantly positively correlated with TWSTRS-1 (severity) score, and significantly negatively correlated with the associated seed-based FC strength.ConclusionsOur results showed signs of both hyper- and hypo-connectivity in bilateral regions of the sensorimotor network related to CD. The imbalance of functional connectivity (both hyper- and hypo-) may hint both overloading and disrupted somatosensory or sensorimotor integration dysfunction within the sensorimotor network underlying the pathophysiology of CD, thus providing a network target for future therapies.     

Decreased functional connectivity of EEG theta-frequency activity in first-episode, neuroleptic-naïve patients with schizophrenia: preliminary results

We explored and refined the hypothesis that during a first episode of acute schizophrenia a disorganization of brain functioning is present. A novel EEG measure was introduced, Global Field Synchronization (GFS), that estimates functional connectivity of brain processes in different EEG frequency bands. The measure was applied to EEG's from 11 never-treated, first-episode, young patients with an acute, positive, schizophrenic symptomatology and from 19 controls, residing in Bern, Switzerland. In comparison to age- and sex- matched controls, patients had significantly decreased GFS in the theta EEG frequency band, indicating a loosened functional connectivity of processes in this frequency. The result was confirmed in an independent, comparable patient group from Osaka, Japan (9 patients and 9 controls), thus making a total of 20 analyzed patients. Previous EEG research in healthy, awake subjects indicated a positive correlation of theta activity with memory functions. Thus, our result suggests a loss of mutual interdependence of memory functions in patients with acute schizophrenia, which agrees well with previous reports of working memory dysfunction in schizophrenia.     

Default-mode network connectivity in cognitively unimpaired drug-naïve patients with rigidity-dominant Parkinson’s disease

Parkinson’s disease (PD) with akinetic rigidity (PD_AR) is more likely to develop cognitive deficits compared to PD with tremor-dominant symptoms (PD_TD). The default mode network (DMN) is highly relevant for cognitive processes, so this study tested the functional connectivity (FC) of DMN in cognitively unimpaired PD_AR patients. Resting-state fMRI data were collected in 21 cognitively unimpaired early stage drug-naïve patients with PD_AR and 21 healthy controls (HC). PD patients were matched closely to HCs for demographic and cognitive variables. FC of DMN was evaluated by seed-based correlation approach. Compared to HCs, despite comparable cognitive performance and no statistically discernible GM volume differences, a disruption in the DMN of PD_AR subjects was detected. A decreased FC of DMN was found, specifically prominent in the posterior DMN. We also found a significantly increased FC of the anterior DMN. Three parts of left medial prefrontal regions (anterior, ventral, and dorsal) had significantly increased FC with the cerebellum. In addition, increased FC values of the anterior and ventral parts were negatively correlated with cognitive scores. An evident decline of FC of posterior DMN and enhanced compensatory FC of anterior DMN suggested an early functional disruption of DMN in PD_AR prior to clinical evidence of cognitive impairment. It could be hypothesized that the dysfunction of DMN connectivity may have a role in the development of cognitive decline in PD. However, further longitudinal studies are warranted to understand the underlying neural mechanisms and their relevance to clinical and cognitive outcomes in PD_AR subtype.     

Impairment of verbal memory and learning in antipsychotic-naïve patients with first-episode schizophrenia

BACKGROUND: Verbal memory deficits are of interest in schizophrenia because of the potential relationship to functional and anatomic mesial temporal lobe pathology in this disorder. The goal of this study was to characterize the nature of verbal memory impairments in antipsychotic-na?ve schizophrenic patients early in the course of illness. METHODS: Neuroleptic-na?ve patients with schizophrenia (n=62) and healthy individuals (n=67), matched on IQ, age, sex, and parental socioeconomic status, were administered the California Verbal Learning Test (CVLT). RESULTS: Schizophrenia participants performed significantly worse than healthy individuals on measures of verbal learning, short- and long-term memory, and immediate attention. Deficits in recall were related to reduced use of organizational strategies to facilitate verbal encoding and retrieval. No group differences were found in rate of forgetting or susceptibility to proactive or retroactive interference. Memory deficits had minimal relation to positive or negative symptom severity. CONCLUSIONS: Schizophrenia is characterized by significant verbal memory dysfunction early in the course of illness prior to treatment with antipsychotic medications. Deficits in consistency of learning over several trials, as well as a strong relationship between semantic organizational strategies and reduced learning capacity, implicate prefrontal dysfunction as a contributor to verbal memory deficits in schizophrenia.     

Combination antiretroviral therapy improves cognitive performance and functional connectivity in treatment-naïve HIV-infected individuals

Our study aimed to investigate the short-term effect of combination antiretroviral therapy (cART) on cognitive performance and functional and structural connectivity and their relationship to plasma levels of antiretroviral (ARV) drugs. Seventeen ARV treatment-naïve HIV-infected individuals (baseline mean CD4 cell count, 479 ± 48 cells/mm³) were age matched with 17 HIV-uninfected individuals. All subjects underwent a detailed neurocognitive and functional assessment and magnetic resonance imaging. HIV-infected subjects were scanned before starting cART and 12 weeks after initiation of treatment. Uninfected subjects were assessed once at baseline. Functional connectivity (FC) was assessed within the default mode network while structural connectivity was assessed by voxel-wise analysis using tract-based spatial statistics (TBSS) and probabilistic tractography within the DMN. Tenofovir and emtricitabine blood concentration were measured at week 12 of cART. Prior to cART, HIV-infected individuals had significantly lower cognitive performance than control subjects as measured by the total Z-score from the neuropsychological tests assessing six cognitive domains (p = 0.020). After 12 weeks of cART treatment, there remained only a weak cognitive difference between HIV-infected and HIV-uninfected subjects (p = 0.057). Mean FC was lower in HIV-infected individuals compared with those uninfected (p = 0.008), but FC differences became non-significant after treatment (p = 0.197). There were no differences in DTI metrics between HIV-infected and HIV-uninfected individuals using the TBSS approach and limited evidence of decreased structural connectivity within the DMN in HIV-infected individuals. Tenofovir and emtricitabine plasma concentrations did not correlate with either cognitive performance or imaging metrics. Conclusions: Twelve weeks of cART improves cognitive performance and functional connectivity in ARV treatment-naïve HIV-infected individuals with relatively preserved immune function. Longer periods of observation are necessary to assess whether this effect is maintained.     

Lower availability of midbrain serotonin transporter between healthy subjects with and without a family history of major depressive disorder – a preliminary two-ligand SPECT study

PurposeSerotonin transporter (SERT) and dopamine transporter (DAT) levels differ in patients with major depressive disorder (MDD) who are in a depressed state in comparison with healthy controls. In addition, a family history of depression is a potent risk factor for developing depression, and inherited vulnerability to serotonergic and dopaminergic dysfunction is suspected in this. The aim of this study was to examine the availabilities of midbrain SERT and striatal DAT in healthy subjects with and without a first-degree family history of MDD.MethodsEight healthy subjects with first-degree relatives with MDD and 16 sex- and age-matched healthy controls were recruited. The availabilities of SERT and DAT were approximated using SPECT, employing [¹²³I] 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) and [^99mTc] TRODAT-1 as the ligands, respectively. There are missing data for one participant with a first-degree family history of MDD from the ADAM study, due to a lack of the radio-ligand at the time of experiment.ResultsSERT availability in the midbrain was significantly lower in subjects with a first-degree family history of MDD than in healthy subjects. However, DAT availability was no different between two groups.ConclusionsThe results with regard to the midbrain SERT level suggest the heritability of MDD.     

Neural oscillations in antipsychotic-naïve patients with a first psychotic episode

Objectives: In chronic schizophrenic psychoses, oscillatory abnormalities predominantly occur in prefrontal cortical regions and are associated with reduced communication across cortical areas. Nevertheless, it remains unclear whether similar alterations can be observed in patients with a first episode of psychosis (FEP), a state characterised by pathological features occurring in both late prodromal patients and initial phases of frank schizophrenic psychoses. Methods: We assessed resting-state electroencephalographic data of 31 antipsychotic-naïve FEP patients and 29 healthy controls (HC). We investigated the three-dimensional (3D) current source density (CSD) distribution and lagged phase synchronisation (LPS) of oscillations across small-scale and large-scale brain networks. We additionally investigated LPS relationships with clinical symptoms using linear mixed-effects models. Results: Compared to HC, FEP patients demonstrated abnormal CSD distributions in frontal areas of the brain; while decreased oscillations were found in the low frequencies, an increase was reported in the high frequencies (P?<?0.01). Patients also exhibited deviant LPS in the high frequencies, whose dynamics changed over increasing 3D cortico-cortical distances and increasing psychotic symptoms. Conclusions: These results indicate that in addition to prefrontal cortical abnormalities, altered synchronised neural oscillations are also present, suggesting possible disruptions in cortico-cortical communications. These findings provide new insights into the pathophysiological mechanisms of emerging schizophrenic psychoses.     

Temporal–occipital glioblastoma presenting with Alice in Wonderland Syndrome in a patient with a long-time history of migraine without aura

ABSTRACT

Alice in Wonderland Syndrome (AIWS) is a rare perceptual disorder characterized by an erroneous perception of the body or the surrounding space. AIWS may be caused by different pathologies, ranging from infections to migraine. We present the case of a 54-year-old man, with a long-time history of migraine without aura, diagnosed with AIWS due to a glioblastoma located in the left temporal–occipital junction. To date, this is the first case of AIWS caused by glioblastoma. This case suggests that to exclude aura-mimic phenomena, a careful diagnostic workup should always be performed even in patients with a long-time history of migraine.     

Different effects of the DRD4 genotype on intrinsic brain network connectivity strength in drug-naïve children with ADHD and healthy controls

Brain Imaging and Behavior - The dopamine D4 receptor gene (DRD4) has been consistently reported to be associated with attention-deficit/hyperactivity disorder (ADHD). Recent studies have linked...     

Predictors of treatment satisfaction in antipsychotic-naïve and previously medicated patients with acute-phase psychosis

Abstract

Background: Treatment satisfaction predicts treatment adherence and long-term outcome for patients with psychosis. It is therefore important to understand the underpinnings of patient satisfaction in psychosis treatment for optimal treatment delivery.

Aims: To examine the associations between satisfaction and level and change in positive symptoms, insight, depression and side effects of antipsychotics in previously medicated and antipsychotic-naïve patients.

Method: Data derive from a randomised trial, with 226 respondents at baseline and 104 at follow-up. The measures were the positive subscale and insight item from the Positive and Negative Syndrome Scale, Calgary Depression Scale, the UKU Consumer Satisfaction Rating Scale, and the UKU side effects scale. Structural equation modelling was used to test the model. The full information maximum likelihood estimator used all available data.

Results: In the sample of 226 patients, 67.3% were male and 44.2% were antipsychotic-naïve. The mean age was 34.1 years. For previously medicated patients, satisfaction was predicted by level of insight (b?=??2.21, β?=??0.42) and reduction in positive symptoms (b?=??0.56, β?=??0.39). For antipsychotic-naïve patients, satisfaction was predicted by level and change of insight (b?=??2.21, β?=??0.46), change in depression (b?=??0.37, β?=??0.26) and side effects (b?=??0.15, β?=??0.30). All predictors were significant at the 0.05 level.

Conclusion: Reducing positive symptoms and side effects are important to enhance patient satisfaction. However, improving insight and reducing depression are more important in antipsychotic-naïve patients.

Trial registration: ClinicalTrials.gov identifier: NCT00932529.     

Naïve Theories of Biology,Physics, and Psychology in Children with ASD

Theory of mind is defined as the understanding that mental states predict and explain people’s behaviors. It develops around the age of 4 but seems to remain deficient in people with ASD, whereas other forms of naïve understanding remain intact. This study compares children with ASD to neurotypical children on tasks measuring naïve psychology, physics, and biology (biological parts). Results suggest that children with ASD only underperform on an implicit false belief task. Performances in naïve biology and physics were equivalent across the two groups and uncorrelated to performance on the false belief task. This confirms that naïve physics and biological reasoning are intact in children with ASD but that tracking false beliefs is challenging for this population.

     

Magnetic resonance imaging volumes of the hippocampus in drug-naïve patients with post-traumatic stress disorder without comorbidity conditions

Most brain imaging studies have showed smaller hippocampal volume in adults with chronic PTSD; however, some other studies have not replicated this finding. Most of these investigations included subjects with other psychiatric comorbidities, such as major depression or alcohol abuse.

The prevalence of psychiatric comorbidities in PTSD is generally high and this makes it difficult, if not impossible, to disentangle the contribution of other disorders to hippocampal volume.

Therefore, the main goal of the current study is to compare hippocampal volumes of healthy subjects and drug-naïve patients with PTSD caused by different types of mixed civilian traumas (i.e. car accident, physical abuse, sudden death of a family member, assault or robbery, natural disaster and traumatic abortion) and without comorbidity conditions.

Magnetic resonance imaging (MRI) was used to measure the hippocampi, total cerebrum, gray matter, white matter and cerebrospinal fluid volumes in 34 patients with single diagnosis of PTSD, and 34 case-matched non-PTSD comparison subjects.

The patients with single diagnosis of PTSD had an 11.8% smaller left hippocampus (p < 0.001) and an 8.7% smaller right hippocampus (p = 0.003) than the healthy controls. The results were controlled for the total brain volume and for gray matter volumes. Subjects with PTSD also displayed lower overall gray matter volume (p = 0.006).

There were no significant correlations between hippocampal volumes and illness duration or severity of PTSD. The findings indicate the presence of smaller hippocampal volumes in drug-naïve patients with single diagnosis of PTSD, compared with healthy subjects.