Markus Thimm

Recovery from hemineglect: differential neurobiological effects of optokinetic stimulation and alertness training.

We prospectively investigated by means of neuropsychological tests and functional magnetic resonance imaging (fMRI) the behavioural and neural effects of a 3-week optokinetic stimulation (OKS) training in 7 patients with chronic visuospatial neglect resulting from right-hemisphere lesions. Behaviourally, OKS caused both a short- and a long-term (4 weeks) improvement of performance in a neglect test battery (compared to a 3-week baseline period). This amelioration of neglect symptoms was associated with increases of neural activity during an fMRI spatial attention task bilaterally in the middle frontal gyrus and the precuneus. Additional left hemisphere increases in neural activity were observed in the cingulate gyrus, angular gyrus, middle temporal gyrus and occipital cortex. This pattern of activation represents a combination of areas normally involved in spatial attention plus a compensatory recruitment of left hemisphere areas. These results were then compared with data from our previous study (Thimm et al., 2006) which employed an alertness training (AIXTENT) with an otherwise identical treatment study design. After the OKS training there was more activation bilaterally in the precuneus than after the AIXTENT training. In contrast, after AIXTENT training there was more activation bilaterally in frontal cortex. Taken together, the results show that amelioration of neglect can be induced by both OKS and alertness training. The data furthermore suggest that the differential activations of frontal or parietal areas may reflect the specific impact of the two types of training either on an anterior system for the control of attention intensity (AIXTENT) or on the posterior system of spatial attention (OKS).

Effects of a CACNA1C genotype on attention networks in healthy individuals.

BACKGROUND Recent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be over-represented in patients with psychosis, including schizophrenia, bipolar disorder and major depressive disorder. In these disorders, attention deficits are among the main cognitive symptoms and have been related to altered neural activity in cerebral attention networks. The particular effect of CACNA1C on neural function, such as attention networks, remains to be elucidated. METHOD The current event-related functional magnetic resonance imaging (fMRI) study investigated the effect of the CACNA1C gene on brain activity in 80 subjects while performing a scanner-adapted version of the Attention Network Test (ANT). Three domains of attention were probed simultaneously: alerting, orienting and executive control of attention. RESULTS Risk allele carriers showed impaired performance in alerting and orienting in addition to reduced neural activity in the right inferior parietal lobule [Brodmann area (BA) 40] during orienting and in the medial frontal gyrus (BA 8) during executive control of attention. These areas belong to networks that have been related to impaired orienting and executive control mechanisms in neuropsychiatric disorders. CONCLUSIONS Our results suggest that CACNA1C plays a role in the development of specific attention deficits in psychiatric disorders by modulation of neural attention networks.

Functional reorganisation in patients with right hemisphere stroke after training of alertness: a longitudinal PET and fMRI study in eight cases.

In patients with alertness deficits due to right hemispheric vascular brain damage, training induced changes in the individual functional networks involved in intrinsic alertness were assessed in a longitudinal positron emission tomography (PET)/fMRI activation study. Patients were trained by administering the alertness routine of the AIXTENT computerized attention training or, in the control condition, by using a computerized training of verbal and topological memory. Before and after the training, both a PET/fMRI and a neuropsychological assessment were carried out. In this paper, we are presenting four patients after alertness training: three, whose alertness performance improved significantly after training, and one, who did not improve. In the patients showing behavioural improvement, the PET/fMRI activation after training revealed partial restitution of the right hemisphere (RH) functional network known to subserve intrinsic alertness in normal subjects, especially in the right dorsolateral or medial frontal cortex. For the patient without behavioural improvement, the PET activation after training showed an increase of activation only in the left hemisphere. Out of the four patients in the memory training control group only one showed significant improvement of alertness. Another patient had an increase of right frontal activation after the training but this did not correspond to behavioural improvement. In a control group of six normal participants, repetition of the alertness activation paradigm in fMRI revealed a decrease of right frontal and parietal activation from the first to a second measurement after 3 weeks, in contrast to the observed training induced effects in the patients.

Differential processing of hierarchical visual stimuli in young and older healthy adults: Implications for pathology

Hierarchical figures in which large (global) forms are constructed from smaller (local) forms (Navon, 1977) have proved valuable in studies of perceptual organisation and hemispheric specialisation in both healthy volunteers and a wide range of neurological and psychiatric patients. In studies using Navon figures, normal young adults typically identify global forms faster than local forms. When the global and local forms are incongruent (e.g., a large E made of smaller Rs), global forms often interfere with local form identification more than vice versa. In two conditions on the same subjects, we contrasted the performance of young (mean age 22 years) and older (mean age 58 years) healthy volunteers on global and local processing. In the directed attention task, subjects were instructed to detect a target letter that occurred at the prespecified local or global level. The young subjects showed, as expected, faster reaction times (RTs) to detect global targets. In contrast, the older subjects showed significantly faster RTs to the local targets. Likewise, in a divided attention task, in which subjects were instructed to detect a target letter that could occur at either the local or the global level, the young adults were slightly quicker to detect the global targets and the older subjects were significantly quicker to detect the local targets. Error rates were generally low and there was no significant speed/accuracy trade-off in either condition. The observed local precedence effects in healthy older subjects were unexpected and are discussed in reference to previous work on differential hemispheric aging. That work has suggested that the left hemisphere is preferentially biased toward local processing and ages relatively slowly while the right hemisphere is biased toward global processing and ages relatively quickly. The implications of such putative differential aging for the interpretation of pathological local/global processing in neurological and psychiatric diseases are also emphasised.

COMT genotype and its role on hippocampal-prefrontal regions in declarative memory.

INTRODUCTION Memory dysfunction is a prominent feature in schizophrenia. Impairments of declarative memory have been consistently linked to alterations especially within hippocampal-prefrontal regions. Due to the high heritability of schizophrenia, susceptibility genes and their modulatory impact on the neural correlates on memory are of major relevance. In the present study the influence of the COMT val(158)met status on the neural correlates of declarative memory was investigated in healthy subjects. METHODS From an initial behavioural sample of 522 healthy individuals (Sheldrick et al., 2008), 84 subjects underwent fMRI scanning while performing a memory encoding and a retrieval task. The COMT val(158)met status was determined for the whole sample and correlated with cortical activation within the group of n=84 individuals. RESULTS There were no effects of COMT status on behavioural performance. For declarative memory processing the number of met alleles predicted circumscribed bilateral insula and anterior hippocampus activations during memory encoding as well as less deactivations within the bilateral posterior parahippocampal gyri during memory retrieval. DISCUSSION Although declarative memory performance was unaffected, the neural correlates within hippocampal-prefrontal regions demonstrate a link between COMT val(158)met carrier status and brain areas associated with declarative memory processing. The study contributes to a better understanding of the role that susceptibility genes might play in the aetiology of schizophrenia.

Menstrual cycle effects on selective attention and its underlying cortical networks

It was the aim of the present study to investigate menstrual cycle effects on selective attention and its underlying functional cerebral networks. Twenty-one healthy, right-handed, normally cycling women were investigated by means of functional magnetic resonance imaging using a go/no-go paradigm during the menstrual, follicular and luteal phase. On the behavioral level there was a significant interaction between visual half field and cycle phase with reaction times to right-sided compared to left-sided stimuli being faster in the menstrual compared to the follicular phase. These results might argue for a more pronounced functional cerebral asymmetry toward the left hemisphere in selective attention during the menstrual phase with low estradiol and progesterone levels. Functional imaging, however, did not reveal clear-cut menstrual phase-related changes in activation pattern in parallel to these behavioral findings. A functional connectivity analysis identified differences between the menstrual and the luteal phase: During the menstrual phase, left inferior parietal cortex showed a stronger negative correlation with the right middle frontal gyrus while the left medial frontal cortex showed a stronger negative correlation with the left middle frontal gyrus. These results can serve as further evidence of a modulatory effect of steroid hormones on networks of lateralized cognitive functions not only by interhemispheric inhibition but also by affecting intrahemispheric functional connectivity.

The impact of dystrobrevin-binding protein 1 (DTNBP1) on neural correlates of episodic memory encoding and retrieval

Episodic memory impairment is a frequently reported symptom in schizophrenia. It has been shown to be associated with reduced neural activity of the hippocampus and prefrontal cortex. Given the high heritability of schizophrenia the question arises if alterations in brain activity are modulated by susceptibility genes and might be detectable in healthy risk allele carriers. The present study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 (P1578) of the dystrobrevin‐binding protein 1 (DTNBP1) on brain activity in 84 healthy subjects assessed by functional magnetic resonance imaging (fMRI) while they performed an episodic memory task comprising encoding and retrieval of faces. During encoding, the group of risk allele carriers (n = 29) showed enhanced neural activity in the left middle frontal gyrus (BA 11) and bilaterally in the cuneus (BA 17, 7) when compared with the nonrisk carrier group (n = 55). During retrieval, the risk group (compared to the non risk group) showed increased right hemispheric neural activity comprising the medial frontal gyrus (BA 9), inferior frontal gyrus (BA 9), and inferior parietal lobule (BA 40). Since there were no behavioral performance differences, increased neural activity of the risk group might be interpreted as a correlate of higher effort or differing cognitive strategies in order to compensate for a genetically determined slight cognitive deficit. Interestingly, the laterality of increased prefrontal activity is in accordance with the well known hemispheric encoding/retrieval asymmetry (HERA) model of episodic memory. Hum Brain Mapp, 2010.

Affect-specific activation of shared networks for perception and execution of facial expressions

Previous studies have shown overlapping neural activations for observation and execution or imitation of emotional facial expressions. These shared representations have been assumed to provide indirect evidence for a human mirror neuron system, which is suggested to be a prerequisite of action comprehension. We aimed at clarifying whether shared representations in and beyond human mirror areas are specifically activated by affective facial expressions or whether they are activated by facial expressions independent of the emotional meaning. During neuroimaging, participants observed and executed happy and non-emotional facial expressions. Shared representations were revealed for happy facial expressions in the pars opercularis, the precentral gyrus, in the superior temporal gyrus/medial temporal gyrus (MTG), in the pre-supplementary motor area and in the right amygdala. All areas showed less pronounced activation in the non-emotional condition. When directly compared, significant stronger neural responses emerged for happy facial expressions in the pre-supplementary motor area and in the MTG than for non-emotional stimuli. We assume that activation of shared representations depends on the affect and (social) relevance of the facial expression. The pre-supplementary motor area is a core-shared representation-structure supporting observation and execution of affective contagious facial expressions and might have a modulatory role during the preparation of executing happy facial expressions.

The effects of a DTNBP1 gene variant on attention networks: an fMRI study

BackgroundAttention deficits belong to the main cognitive symptoms of schizophrenia and come along with altered neural activity in previously described cerebral networks. Given the high heritability of schizophrenia the question arises if impaired function of these networks is modulated by susceptibility genes and detectable in healthy risk allele carriers.MethodsThe present event-related fMRI study investigated the effect of the single nucleotide polymorphism (SNP) rs1018381 of the DTNBP1 (dystrobrevin-binding protein 1) gene on brain activity in 80 subjects while performing the attention network test (ANT). In this reaction time task three domains of attention are probed simultaneously: alerting, orienting and executive control of attention.ResultsRisk allele carriers showed impaired performance in the executive control condition associated with reduced neural activity in the left superior frontal gyrus [Brodmann area (BA) 9]. Risk allele carriers did not show alterations in the alerting and orienting networks.ConclusionsBA 9 is a key region of schizophrenia pathology and belongs to a network that has been shown previously to be involved in impaired executive control mechanisms in schizophrenia. Our results identified the impact of DTNBP1 on the development of a specific attention deficit via modulation of a left prefrontal network.

Effect of the G72 (DAOA) putative risk haplotype on cognitive functions in healthy subjects

BackgroundIn the last years, several susceptibility genes for psychiatric disorders have been identified, among others G72 (also named D-amino acid oxidase activator, DAOA). Typically, the high-risk variant of a vulnerability gene is associated with decreased cognitive functions already in healthy individuals. In a recent study however, a positive effect of the high-risk variant of G72 on verbal working memory was reported. In the present study, we therefore examined the relationship between G72 genotype status and a broad range of cognitive functions in 423 healthy individuals.MethodsThe G72 carrier status was assessed by the two single nucleotide polymorphisms (SNPs) M23 and M24. Subjects were divided into three risk groups (low, intermediate and high risk).ResultsG72 status influenced a number of cognitive functions, such as verbal working memory, attention, and, at a trend level, spatial working memory and executive functions. Interestingly, the high-risk allele carriers scored better than one or even both other groups.ConclusionOur data show that the putative high-risk haplotype (i.e. homozygote C/C-allele carriers in SNP M23 and homozygote T/T-allele carriers in SNP M24) is in healthy individuals not necessarily associated with worse performance in cognitive functions, but even with better performance in some domains. Further work is required to identify the mechanisms of G72 on brain functions.