The effect of second-generation antipsychotics on basal ganglia and thalamus in first-episode psychosis patients.

Patients who have recently experienced a first of episode psychosis (FEP) exhibit considerable heterogeneity in subcortical brain volumes. These results become even more divergent when exploring the effect of antipsychotic medication among other clinical and cognitive features. We aimed to contrast volumetric measures in basal ganglia and thalamus in patients with a FEP treated with different second-generation antipsychotics. T1-weighted magnetic resonance images were obtained and subcortical structures were extracted with MAGeT-Brain. Relationships with cognitive functioning were also explored with a Global Cognitive Index obtained, on average, within one month from the scan. Subgroups included: risperidone (n = 26), aripiprazole (n = 22), olanzapine (n = 19) and controls (n = 80). The olanzapine subgroup displayed significant enlargement of the right globus pallidus volume compared with all other groups. Moreover, despite not exhibiting poorer cognitive capacity than the rest of patients, results from a stepwise multiple-regression linear regression analysis identified a significant negative association between right globus pallidus volume and scores on the Global Cognitive Index among these patients. To our knowledge, this is the first study to associate treatment with olanzapine with an increase in globus pallidus volume in a sample of FEP patients with a relatively short time of antipsychotic monotherapy. Such enlargement was also found to be associated with poorer global cognitive functioning. Exploration of the biological underpinnings of this early medication-induced enlargement should be the focus of future investigations since it may lend insight towards achieving a better clinical outcome for these patients.

Clarifying associations between cortical thickness, subcortical structures, and a comprehensive assessment of clinical insight in enduring schizophrenia.

BACKGROUND: The relationship between poor insight and less favorable outcomes in schizophrenia has promoted research efforts to understand its neurobiological basis. Thus far, research on neural correlates of insight has been constrained by small samples, incomplete insight assessments, and a focus on frontal lobes. The purpose of this study was to examine associations of cortical thickness and subcortical volumes, with a comprehensive assessment of clinical insight, in a large sample of enduring schizophrenia patients. METHODS: Two dimensions of clinical insight previously identified by a factor analysis of 4 insight assessments were used: Awareness of Illness and Need for Treatment (AINT) and Awareness of Symptoms and Consequences (ASC). T1-weighted structural images were acquired on a 3 T MRI scanner for 110 schizophrenia patients and 69 healthy controls. MR images were processed using CIVET (version 2.0) and MAGeT and quality controlled pre and post-processing. Whole-brain and region-of-interest, vertex-wise linear models were applied between cortical thickness, and levels of AINT and ASC. Partial correlations were conducted between volumes of the amygdala, thalamus, striatum, and hippocampus and insight levels. RESULTS: No significant associations between both insight factors and cortical thickness were observed. Moreover, no significant associations emerged between subcortical volumes and both insight factors. CONCLUSIONS: These results do not replicate previous findings obtained with smaller samples using single-item measures of insight into illness, suggesting a limited role of neurobiological factors and a greater role of psychological processes in explaining levels of clinical insight.

Ketogenic Medium Chain Triglycerides Increase Brain Energy Metabolism in Alzheimer's Disease.

BACKGROUND: In Alzheimer's disease (AD), it is unknown whether the brain can utilize additional ketones as fuel when they are derived from a medium chain triglyceride (MCT) supplement. OBJECTIVE: To assess whether brain ketone uptake in AD increases in response to MCT as it would in young healthy adults. METHODS: Mild-moderate AD patients sequentially consumed 30 g/d of two different MCT supplements, both for one month: a mixture of caprylic (55%) and capric acids (35%) (n = 11), followed by a wash-out and then tricaprylin (95%; n = 6). Brain ketone (11C-acetoacetate) and glucose (FDG) uptake were quantified by PET before and after each MCT intervention. RESULTS: Brain ketone consumption doubled on both types of MCT supplement. The slope of the relationship between plasma ketones and brain ketone uptake was the same as in healthy young adults. Both types of MCT increased total brain energy metabolism by increasing ketone supply without affecting brain glucose utilization. CONCLUSION: Ketones from MCT compensate for the brain glucose deficit in AD in direct proportion to the level of plasma ketones achieved.

Evaluating accuracy of striatal, pallidal, and thalamic segmentation methods: Comparing automated approaches to manual delineation.

Accurate automated quantification of subcortical structures is a greatly pursued endeavour in neuroimaging. In an effort to establish the validity and reliability of these methods in defining the striatum, globus pallidus, and thalamus, we investigated differences in volumetry between manual delineation and automated segmentations derived by widely used FreeSurfer and FSL packages, and a more recent segmentation method, the MAGeT-Brain algorithm. In a first set of experiments, the basal ganglia and thalamus of thirty subjects (15 first episode psychosis [FEP], 15 controls) were manually defined and compared to the labels generated by the three automated methods. Our results suggest that all methods overestimate volumes compared to the manually derived "gold standard", with the least pronounced differences produced using MAGeT. The least between-method variability was noted for the striatum, whereas marked differences between manual segmentation and MAGeT compared to FreeSurfer and FSL emerged for the globus pallidus and thalamus. Correlations between manual segmentation and automated methods were strongest for MAGeT (range: 0.51 to 0.92; p<0.01, corrected), whereas FreeSurfer and FSL showed moderate to strong Pearson correlations (range 0.44-0.86; p<0.05, corrected), with the exception of FreeSurfer pallidal (r=0.31, p=0.10) and FSL thalamic segmentations (r=0.37, p=0.051). Bland-Altman plots highlighted a tendency for greater volumetric differences between manual labels and automated methods at the lower end of the distribution (i.e. smaller structures), which was most prominent for bilateral thalamus across automated pipelines, and left globus pallidus for FSL. We then went on to examine volume and shape of the basal ganglia structures using automated techniques in 135 FEP patients and 88 controls. The striatum and globus pallidus were significantly larger in FEP patients compared to controls bilaterally, irrespective of the method used. MAGeT-Brain was more sensitive to shape-based group differences, and uncovered widespread surface expansions in the striatum and globus pallidus bilaterally in FEP patients compared to controls, and surface contractions in bilateral thalamus (FDR-corrected). By contrast, after using a recommended cluster-wise thresholding method, FSL only detected differences in the right ventral striatum (FEP>Control) and one cluster of the left thalamus (Control>FEP). These results suggest that different automated pipelines segment subcortical structures with varying degrees of variability compared to manual methods, with particularly pronounced differences found with FreeSurfer and FSL for the globus pallidus and thalamus.

Parietal cortex and episodic memory retrieval in schizophrenia.

People with schizophrenia consistently show memory impairment on varying tasks including item recognition memory. Relative to the correct rejection of distracter items, the correct recognition of studied items consistently produces an effect termed the old/new effect that is characterized by increased activity in parietal and frontal cortical regions. This effect has received only scant attention in schizophrenia. We examined the old/new effect in 15 people with schizophrenia and 18 controls during an item recognition test, and neural activity was examined with event-related functional magnetic resonance imaging. Both groups performed equally well during the recognition test and showed increased activity in a left dorsolateral prefrontal region and in the precuneus bilaterally during the successful recognition of old items relative to the correct rejection of new items. The control group also exhibited increased activity in the dorsal left parietal cortex. This region has been implicated in the top-down modulation of memory which involves control processes that support memory-retrieval search, monitoring and verification. Although these processes may not be of paramount importance in item recognition memory performance, the present findings suggest that people with schizophrenia may have difficulty with such top-down modulation, a finding consistent with many other studies in information processing.

Apomorphine effects on episodic memory in young healthy volunteers.

RATIONALE: Dopamine (DA) modulates working memory. However, the relation between DA systems and episodic (declarative) memory is less established. Frontal lobe DA function may be involved. We were interested in assessing whether apomorphine (Apo), a drug used extensively in clinical research as a probe of DA function, has an effect on episodic memory test performance in healthy volunteers. OBJECTIVE: To investigate the effect of a presynaptic dose of Apo on episodic memory tests and on other tests thought to be sensitive to frontal lobe functions. METHODS: Twenty healthy subjects were treated with Apo HCl (5 microg/kg sc) or placebo (10 subjects/group) in a randomized, double blind parallel group design and performance on a battery of cognitive tests was assessed. RESULTS: Apomorphine significantly impaired performance on tests of source recognition (d.f.=19, p=0.05) and item recognition memory (d.f.=19, p<0.05), and memory interference (d.f.=19, p<0.010). No significant change was found on other tests (Go/no-Go Test, Categorized Words, Stroop, Trail Making Test, and verbal fluency). CONCLUSION: Findings in this small sample of subjects suggest that dopaminergic transmission affects episodic memory functions.

MRI observation of the light-induced release of a contrast agent from photo-controllable polymer micelles.

The encapsulation of molecules into nanocarriers is studied for its potential in delivering a high dose of anticancer drugs to a tumor, while minimizing side effects. Most systems either release their content in a non-specific manner or under specific environmental conditions such as temperature or pH. We have synthesized a novel class of photo-controllable polymer micelles that can stably encapsulate a hydrophilic compound and subsequently release it upon absorption of UV light. Here, we describe an in vitro magnetic resonance imaging assay that can evaluate the state of incorporation of a small Gd-based contrast agent. Our results indicate that the contrast agent alone can diffuse through a filter, but that the same agent incorporated into micelles cannot. After exposure to UV light, the micelles released the contrast agent, which could then diffuse through the filter.