Thalamic Shape Abnormalities Differentially Relate to Cognitive Performance in Early-Onset and Adult-Onset Schizophrenia.

Early-onset schizophrenia (EOS) shares many biological and clinical features with adult-onset schizophrenia (AOS), but may represent a unique subgroup with greater susceptibility for disease onset and worsened symptomatology and progression, which could potentially derive from exaggerated neurodevelopmental abnormalities. Neurobiological explanations of schizophrenia have emphasized the involvement of deep-brain structures, particularly alterations of the thalamus, which have been linked to core features of the disorder. The aim of this study was to compare thalamic shape abnormalities between EOS and AOS subjects and determine whether unique behavioral profiles related to these differences. It was hypothesized abnormal thalamic shape would be observed in anterior, mediodorsal and pulvinar regions in both schizophrenia groups relative to control subjects, but exacerbated in EOS. Magnetic resonance T1-weighted images were collected from adult individuals with EOS (n = 28), AOS (n = 33), and healthy control subjects (n = 60), as well as collection of clinical and cognitive measures. Large deformation high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. General linear models were used to compare groups on surface shape features, and Pearson correlations were used to examine relationships between thalamic shape and behavioral measures. Results revealed both EOS and AOS groups demonstrated significant abnormal shape of anterior, lateral and pulvinar thalamic regions relative to CON (all p < 0.007). Relative to AOS, EOS exhibited exacerbated abnormalities in posterior lateral, mediodorsal and lateral geniculate thalamic regions (p = 0.003). Thalamic abnormalities related to worse episodic memory in EOS (p = 0.03) and worse working memory (p = 0.047) and executive functioning (p = 0003) in AOS. Overall, findings suggest thalamic abnormalities are a prominent feature in both early- and late-onset schizophrenia, but exaggerated in EOS and have different brain-behavior profiles for each. The persistence of these abnormalities in adult EOS patients suggests they may represent markers of disrupted neurodevelopment that uniquely relate to the clinical and cognitive aspects of the illness.

Task-related fMRI responses to a nicotinic acetylcholine receptor partial agonist in schizophrenia: A randomized trial.

INTRODUCTION: AQW051, an α7-nicotinic acetylcholine receptor partial agonist, enhanced cognitive function in rodent models of learning and memory. This study evaluated brain activation during performance of a working memory task (WMT) and an episodic memory task (EMT), and the effect of AQW051 on task-related brain activation and performance in subjects with schizophrenia. METHODS: This was a double-blind, randomized, placebo-controlled, multicenter, 2-period cross-over trial (NCT00825539) in participants with chronic, stable schizophrenia. Participants, stratified according to smoking status, were randomized (1:1:1:1:1:1) to 1 of 6 sequence groups that determined the study drug dose (AQW051 7.5mg, 50mg or 100mg) and order of administration versus placebo. The primary outcome was brain activation in a priori target regions of interest (ROIs) during performance of the WMT and EMT, measured using functional magnetic resonance imaging. The effect of AQW051 on task-related (EMT and WMT) brain activation and performance was also assessed, as were safety and tolerability. RESULTS: Overall, 60 of 68 enrolled participants completed the study (AQW051 then placebo: 7.5mg n=9; 50mg n=11; 100mg n=10. Placebo then AQW051: 7.5mg n=10; 50mg n=11; 100mg n=9). Significant task-related brain activation (5% significance level) was observed with placebo. During the WMT, a medium effect size was observed in the inferior prefrontal cortex with AQW051 100mg versus placebo (0.431; p=0.105). During the EMT encoding phase, a large effect size was observed in the anterior hippocampus (0.795; p=0.007) and a medium effect size in the posterior hippocampus (0.476; p=0.079) with AQW051 7.5mg. No other medium/large effect sizes were observed with any dose on either task. Effects on brain activation were generally not associated with changes in cognitive performance. AQW051 was well tolerated with an acceptable safety profile. CONCLUSIONS: Overall, no consistent effects of AQW051 on brain regions involved in the performance of a WMT or EMT were observed; however, this study presents a model for evaluating potential response to pharmacological interventions for cognitive impairment in schizophrenia.

Schizophrenia Pharmacology: Past, Present, and Future Targets for Intervention.

The first medication for schizophrenia was discovered serendipitously. Years later, it was shown that the medication worked by blocking dopamine, and to this date, all available antipsychotic medications also work by blocking dopamine. They differ, however, in many other respects. The so-called first-generation medications have a wide range of receptor affinities, but in all cases, they have a higher affinity for dopamine receptors than for serotonin receptors. In contrast, so-called second-generation medications have a higher affinity for serotonin receptors than for dopamine receptors. A third category of medication acts as a partial agonist at the dopamine receptor. It is likely that a fourth category will also become available and these medications will act as agonists at the N-methyl-d-aspartate receptor, although clinical trials thus far have struggled to demonstrate efficacy. In addition to medications that treat symptoms of psychosis, medications are under development to directly target some of the more fundamental aspects of cognition that are impaired in schizophrenia, including memory, sensory processing, attention, and executive function. Several promising strategies are discussed.

Cannabis-related working memory deficits and associated subcortical morphological differences in healthy individuals and schizophrenia subjects.

Cannabis use is associated with working memory (WM) impairments; however, the relationship between cannabis use and WM neural circuitry is unclear. We examined whether a cannabis use disorder (CUD) was associated with differences in brain morphology between control subjects with and without a CUD and between schizophrenia subjects with and without a CUD, and whether these differences related to WM and CUD history. Subjects group-matched on demographics included 44 healthy controls, 10 subjects with a CUD history, 28 schizophrenia subjects with no history of substance use disorders, and 15 schizophrenia subjects with a CUD history. Large-deformation high-dimensional brain mapping with magnetic resonance imaging was used to obtain surface-based representations of the striatum, globus pallidus, and thalamus, compared across groups, and correlated with WM and CUD history. Surface maps were generated to visualize morphological differences. There were significant cannabis-related parametric decreases in WM across groups. Similar cannabis-related shape differences were observed in the striatum, globus pallidus, and thalamus in controls and schizophrenia subjects. Cannabis-related striatal and thalamic shape differences correlated with poorer WM and younger age of CUD onset in both groups. Schizophrenia subjects demonstrated cannabis-related neuroanatomical differences that were consistent and exaggerated compared with cannabis-related differences found in controls. The cross-sectional results suggest that both CUD groups were characterized by WM deficits and subcortical neuroanatomical differences. Future longitudinal studies could help determine whether cannabis use contributes to these observed shape differences or whether they are biomarkers of a vulnerability to the effects of cannabis that predate its misuse.

Alcohol use disorders contribute to hippocampal and subcortical shape differences in schizophrenia.

BACKGROUND: Alcohol abuse and dependence have been reported to exacerbate the clinical course of schizophrenia. However, the neurobiological basis of this co-morbid interaction is unknown. The aim of this study was to determine the relationship of co-morbid alcohol use disorder (AUD) with brain structure abnormalities in schizophrenia patients. METHODS: T1-weighted magnetic resonance images were collected from schizophrenia patients without a history of any substance use disorder (SCZ_0, n=35), schizophrenia patients with a history of AUD only (SCZ_AUD, n=16), and a healthy comparison group without a history of any substance use disorder (CON, n=56). Large-deformation, high-dimensional brain mapping was used to quantify the surface shapes of the hippocampus, thalamus, striatum, and globus pallidus in these subject groups. Analysis of variance was used to test for differences in surface shape measures among the groups. RESULTS: SCZ_AUD demonstrated the greatest severity of shape abnormalities in the hippocampus, thalamus, striatum, and globus pallidus as compared to SCZ_0 and CON. SCZ_AUD demonstrated a combination of exaggerated shape differences in regions where SCZ_0 also showed shape differences, and unique shape differences that were not observed in SCZ_0 or CON. CONCLUSIONS: Shape differences in schizophrenia were compounded by a history of co-morbid AUD. Future research is needed to determine whether these differences are simply additive or whether they are due to an interaction between the underlying neurobiology of schizophrenia and alcoholism. The consequences of such shape differences for the clinical course of schizophrenia are not yet understood.

Thalamic morphology in schizophrenia and schizoaffective disorder.

BACKGROUND: Biomarkers are needed that can distinguish between schizophrenia and schizoaffective disorder to inform the ongoing debate over the diagnostic boundary between these two disorders. Neuromorphometric abnormalities of the thalamus have been reported in individuals with schizophrenia and linked to core features of the disorder, but have not been similarly investigated in individuals with schizoaffective disorder. In this study, we examine whether individuals with schizoaffective disorder have a pattern of thalamic deformation that is similar or different to the pattern found in individuals with schizophrenia. METHOD: T1-weighted magnetic resonance images were collected from individuals with schizophrenia (n = 47), individuals with schizoaffective disorder (n = 15), and controls (n = 42). Large-deformation, high-dimensional brain mapping was used to obtain three-dimensional surfaces of the thalamus. Multiple analyses of variance were used to test for group differences in volume and measures of surface shape. RESULTS: Individuals with schizophrenia or schizoaffective disorder have similar thalamic volumes. Thalamic surface shape deformation associated with schizophrenia suggests selective involvement of the anterior and posterior thalamus, while deformations in mediodorsal and ventrolateral regions were observed in both groups. Schizoaffective disorder had distinct deformations in medial and lateral thalamic regions. CONCLUSIONS: Abnormalities distinct to schizoaffective disorder suggest involvement of the central and ventroposterior medial thalamus which may be involved in mood circuitry, dorsolateral nucleus which is involved in recall processing, and the lateral geniculate nucleus which is involved in visual processing.

Thalamic pathology in schizophrenia.

The thalamus plays a critical role in the coordination of information as it passes from region to region within the brain. A disruption of that information flow may give rise to some of the cardinal symptoms of schizophrenia. In support of this hypothesis, schizophrenia-like syndromes emerge when illnesses, such as stroke, selectively damage the thalamus while sparing the rest of the brain. Evidence from many sources has implicated thalamic dysfunction in schizophrenia. In postmortem studies, several subregions of the thalamus, including the mediodorsal nucleus and the pulvinar, have been shown to have fewer neurons in schizophrenia. Neurochemical disturbances are also seen, with changes in both the glutamate and dopamine systems; thalamic glutamate receptor expression is altered in schizophrenia, and dopamine appears to be elevated in thalamic subregions, while evidence exists of an imbalance between dopamine and other neurotransmitters. In vivo studies using magnetic resonance imaging have demonstrated smaller thalamic volumes in schizophrenia, as well as shape deformations suggesting changes in those thalamic regions that are most densely connected to the portions of the brain responsible for executive function and sensory integration. These changes seem to be correlated with clinical symptoms. The thalamus is a starting point for several parallel, overlapping networks that extend from thalamic nuclei to the cortex. Evidence is emerging that changes in the thalamic nodes of these networks are echoed by changes at other points along the chain; this suggests that schizophrenia might be a disease of disrupted thalamocortical neural networks. This model distributes the pathology throughout the network, but also concentrates attention on the thalamus as a critical structure, especially because of its role in coordinating the flow of information within and between neural networks.