Step away from depression-results from a multicenter randomized clinical trial with a pedometer intervention during and after inpatient treatment of depression.

Evidence for the effectiveness of physical activity (PA) in the treatment of depression prevails for outpatients with mild and moderate symptom levels. For inpatient treatment of severe depression, evidence-based effectiveness exists only for structured and supervised group PA interventions. The Step Away from Depression (SAD) study investigated the effectiveness of an individual pedometer intervention (PI) combined with an activity diary added to inpatient treatment as usual (TAU). In this multicenter randomized controlled trial, 192 patients were randomized to TAU or TAU plus PI. The two primary outcomes at discharge were depression-blindly rated with the Montgomery-Åsberg Depression Rating Scale (MADRS)-and average number of daily steps measured by accelerometers. Secondary outcomes were self-rated depression and PA, anxiety, remission and response rates. Multivariate analysis of variance (MANOVA) revealed no significant difference between both groups for depression and daily steps. Mean MADRS scores at baseline were 29.5 (SD = 8.3) for PI + TAU and 28.8 (SD = 8.1) for TAU and 16.4 (SD = 10.3) and 17.2 (SD = 9.9) at discharge, respectively. Daily steps rose from 6285 (SD = 2321) for PI + TAU and 6182 (SD = 2290) for TAU to 7248 (SD = 2939) and 7325 (SD = 3357). No differences emerged between groups in secondary outcomes. For severely depressed inpatients, a PI without supervision or further psychological interventions is not effective. Monitoring, social reinforcement and motivational strategies should be incorporated in PA interventions for this population to reach effectiveness.

Depression and fatigue in active IBD from a microbiome perspective-a Bayesian approach to faecal metagenomics.

BACKGROUND: Extraintestinal symptoms are common in inflammatory bowel diseases (IBD) and include depression and fatigue. These are highly prevalent especially in active disease, potentially due to inflammation-mediated changes in the microbiota-gut-brain axis. The aim of this study was to investigate the associations between structural and functional microbiota characteristics and severity of fatigue and depressive symptoms in patients with active IBD. METHODS: We included clinical data of 62 prospectively enrolled patients with IBD in an active disease state. Patients supplied stool samples and completed the questionnaires regarding depression and fatigue symptoms. Based on taxonomic and functional metagenomic profiles of faecal gut microbiota, we used Bayesian statistics to investigate the associative networks and triangle motifs between bacterial genera, functional modules and symptom severity of self-reported fatigue and depression. RESULTS: Associations with moderate to strong evidence were found for 3 genera (Odoribacter, Anaerotruncus and Alistipes) and 3 functional modules (pectin, glycosaminoglycan and central carbohydrate metabolism) with regard to depression and for 4 genera (Intestinimonas, Anaerotruncus, Eubacterium and Clostridiales g.i.s) and 2 functional modules implicating amino acid and central carbohydrate metabolism with regard to fatigue. CONCLUSIONS: This study provides the first evidence of association triplets between microbiota composition, function and extraintestinal symptoms in active IBD. Depression and fatigue were associated with lower abundances of short-chain fatty acid producers and distinct pathways implicating glycan, carbohydrate and amino acid metabolism. Our results suggest that microbiota-directed therapeutic approaches may reduce fatigue and depression in IBD and should be investigated in future research.

Exploring joint patterns of brain structure and function in inflammatory bowel diseases using multimodal data fusion.

BACKGROUND: A growing number of neuroimaging studies suggest distinct neural changes in inflammatory bowel diseases (IBDs). Whether such changes may show similar spatial patterns across distinct neural features within and between specific IBD is unclear. To address this question, we used multivariate multimodal data fusion analysis to investigate structure/function modulation in remitted patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: Patients with IBD (n = 46; n = 31 with CD, n = 15 with UC) in stable remission and 17 healthy controls (HC) underwent structural magnetic resonance imaging (sMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) as well as cognitive testing. Anxiety, depression, and fatigue were assessed using self-rating questionnaires. sMRI data were analyzed via voxel-based morphometry (VBM) and rs-fMRI data via amplitude of low-frequency fluctuations (ALFFs) and regional homogeneity (ReHo). Detection of cross-information between VBM, ALFF, and ReHo was conducted by means of a joint independent component analysis (jICA), followed by group-inference statistics. KEY RESULTS: Joint independent component analysis detected structural alterations in middle frontal and temporal regions (VBM), and functional changes in the superior frontal gyrus (ReHo) and the medial as well as inferior frontal, inferior temporal, rectal, and subcallosal gyrus (ALFF). One joint component of extracted features of the three modalities differed significantly between IBD patients and controls (p = 0.03), and most distinctly between HC and patients with UC. CONCLUSIONS AND INFERENCES: Using a multivariate data fusion technique, this study provides further evidence to brain alterations in IBD. The data suggest distinct neural differences between CD and UC, particularly in frontotemporal regions.

Transdiagnostic modulation of brain networks by electroconvulsive therapy in schizophrenia and major depression.

Major depressive disorder (MDD) and schizophrenia (SCZ) share neurobiological and clinical commonalities. Altered functional connectivity of large-scale brain networks has been associated with both disorders. Electroconvulsive therapy (ECT) has proven to be an effective treatment in severe forms of MDD and SCZ. However, the role of ECT on the modulation of the dynamics of brain networks is still unknown. In this study, we used resting state functional magnetic resonance imaging (rs-fMRI) to investigate functional connectivity in 16 pharmacoresistant patients with SCZ or MDD and a matched group of normal controls. Patients were scanned before and after right-sided unilateral ECT. Group spatial independent component analysis was carried out with a multiple analysis of covariance (MANCOVA) approach to estimate the effects of ECT treatment on intrinsic components (INs). Functional network connectivity (FNC) was calculated between pairs of INs. Patients had reduced connectivity within a striato-thalamic network in the thalamus as well as increased low frequency oscillations in a striatal network. ECT reduced low frequency oscillations (LFOs) on a striatal network along with increasing functional connectivity in the medial prefrontal cortex within the DMN. Following ECT treatment, the FNC of the executive network was reduced with the DMN and increased with the salience network, respectively. Our findings suggest transnosological effects of ECT on the connectivity of large-scale networks as well as at the level of their interplay. Furthermore, they support a transnosological approach for the investigation not only of the neural correlates of the disease but also of the brain mechanism of treatment of mental disorders.

Neuromodulation in response to electroconvulsive therapy in schizophrenia and major depression.

BACKGROUND: Electroconvulsive therapy (ECT) is one of the most effective treatments in severe and treatment-resistant major depressive disorder (MDD). ECT has been also shown to be effective in schizophrenia (SZ), particularly when rapid symptom reduction is needed or in cases of resistance to drug-treatment. However, its precise mechanisms of action remain largely unknown. OBJECTIVE/HYPOTHESIS: This study examined whether ECT exerts disorder-specific or unspecific modulation of brain structure and function in SZ and MDD. METHODS: We investigated neuromodulatory effects of right-sided unilateral ECT in pharmacoresistant patients with SZ or MDD. Magnetic resonance imaging was conducted before and after ECT to investigate treatment-related effects on brain structure and function. Imaging data were analyzed by means of Voxel Based Morphometry and Resting State Functional Connectivity (RSFC) methods. RESULTS: Right unilateral ECT induced transdiagnostic regional increases of limbic gray matter and modulations of neural coupling at rest. Structural effects were accompanied by a decrease in RSFC within temporoparietal, prefrontal and cortical midline structures, and an increase in hypothalamic RSFC. The extent of structural and functional change was partially inversely associated with the baseline measures. CONCLUSION: The present findings provide first evidence for transdiagnostic changes of brain structure together with modulation of brain function after ECT. The data indicate diagnosis-unspecific mechanisms of action with respect to regional gray matter volume and resting-state functional connectivity.

Structural network changes in patients with major depression and schizophrenia treated with electroconvulsive therapy.

Electroconvulsive therapy (ECT) is one of the most effective treatments in severe and treatment-resistant major depressive disorder (MDD). In schizophrenia (SZ), ECT is frequently considered in drug-resistant cases, as an augmentation of antipsychotic treatment or in cases when rapid symptom relief is indicated. Accumulating neuroimaging evidence suggests modulation of medial temporal lobe and prefrontal cortical regions in MDD by ECT. In SZ, ECT-effects on brain structure have not been systematically investigated so far. In this study, we investigated brain volume in 21 ECT-naïve patients (12 with MDD, 9 with SZ) who received right-sided unilateral ECT. Twenty-one healthy controls were included. Structural magnetic resonance imaging data were acquired before and after ECT. Healthy participants were scanned once. Source-based morphometry was used to investigate modulation of structural networks pre/post ECT. ECT had an impact on distinct structural networks in MDD and SZ. In both MDD and SZ SBM revealed a medial temporal lobe (MTL) network (including hippocampus and parahippocampal cortex) which showed a significant increase after ECT. The increase in MTL network strength was not associated with clinical improvement in either MDD or SZ. In SZ a lateral prefrontal/cingulate cortical network showed a volume increase after ECT, and this effect was accompanied by clinical improvement. These findings provide preliminary evidence for structural network change in response to ECT in MDD and SZ. The data suggest both diagnosis-specific and transdiagnostic ECT-effects on brain volume. In contrast to SZ, in MDD structural network modulation by ECT was not associated with clinical improvement.

Evidence for Distinguishable Treatment Costs among Paranoid Schizophrenia and Schizoaffective Disorder.

BACKGROUND: Schizophrenia spectrum disorders result in enormous individual suffering and financial burden on patients and on society. In Germany, there are about 1,000,000 individuals suffering from schizophrenia (SZ) or schizoaffective disorder (SAD), a combination of psychotic and affective symptoms. Given the heterogeneous nature of these syndromes, one may assume that there is a difference in treatment costs among patients with paranoid SZ and SAD. However, the current the national system of cost accounting in psychiatry and psychosomatics in Germany assesses all schizophrenia spectrum disorders within one category. METHODS: The study comprised a retrospective audit of data from 118 patients diagnosed with paranoid SZ (F20.0) and 71 patients with SAD (F25). We used the mean total costs as well as partial cost, i.e., mean costs for medication products, mean personal costs and mean infrastructure costs from each patient for the statistical analysis. We tested for differences in the four variables between SZ and SAD patients using ANCOVA and confirmed the results with bootstrapping. RESULTS: SAD patients had a longer duration of stay than patients with SZ (p = .02). Mean total costs were significantly higher for SAD patients (p = .023). Further, we found a significant difference in mean personnel costs (p = .02) between patients with SZ and SAD. However, we found no significant differences in mean pharmaceutical costs (p = .12) but a marginal difference of mean infrastructure costs (p = .05) between SZ and SAD. We found neither a common decrease of costs over time nor a differential decrease in SZ and SAD. CONCLUSION: We found evidence for a difference of case related costs of inpatient treatments for paranoid SZ and SAD. The differences in mean total costs seem to be primarily related to the mean personnel costs in patients with paranoid SZ and SAD rather than mean pharmaceutical costs, possibly due to higher personnel effort and infrastructure.

Neuropsychology, autobiographical memory, and hippocampal volume in "younger" and "older" patients with chronic schizophrenia.

Despite a wide range of studies on neuropsychology in schizophrenia, autobiographical memory (AM) has been scarcely investigated in these patients. Hence, less is known about AM in older patients and hippocampal contribution to autobiographical memories of varying remoteness. Therefore, we investigated hippocampal volume and AM along with important neuropsychological domains in patients with chronic schizophrenia and the respective relationships between these parameters. We compared 25 older patients with chronic schizophrenia to 23 younger patients and an older healthy control group (N = 21) with respect to AM, additional neuropsychological parameters, and hippocampal volume. Personal episodic and semantic memory was investigated using a semi-structured interview. Additional neuropsychological parameters were assessed by using a battery of standard neuropsychological tests. Structural magnetic resonance imaging data were analyzed with an automated region-of-interest procedure. While hippocampal volume reduction and neuropsychological impairment were more pronounced in the older than in the younger patients, both groups showed equivalent reduced AM performance for recent personal episodes. In the patient group, significant correlations between left hippocampal volume and recent autobiographical episodes as well as personal semantic memories arose. Verbal memory and working memory were significantly correlated with right hippocampal volume; executive functions, however, were associated with bilateral hippocampal volumes. These findings underline the complexity of AM and its impairments in the course of schizophrenia in comparison to rather progressive neuropsychological deficits and address the importance of hippocampal contribution.

Abnormal cerebellar volume and corticocerebellar dysfunction in early manifest Huntington's disease.

Evidence from animal models and neuropathological data has revealed cerebellar pathology in Huntington's disease (HD). The extent of cerebellar dysfunction in preclinical stages and in early manifest HD is unclear. In this study, using MRI we investigated cerebellar changes in preclinical (preHD) and early manifest HD individuals. High-resolution structural MRI data at 3 Tesla were obtained from two independent preHD samples (n = 20/25 participants), from two independent cohorts of healthy controls (n = 20/24 participants) and from patients with early manifest HD (n = 20 participants). Resting-state functional MRI data were acquired from 20 healthy controls and 20 HD patients. Cerebellar volume was investigated using cerebellum-optimized voxel-based analysis methods. Corticocerebellar connectivity at rest was investigated by means of seed-region correlations. In both preHD samples, between-group analyses revealed no change of cerebellar volume. In contrast, early manifest HD patients exhibited lower right cerebellar lobule VIIa volume (p < 0.05 cluster-corrected). Within the control group regions functionally coupled to right cerebellar lobule VII comprised bilateral cerebellar regions, right prefrontal and cingulate areas, whereas within manifest HD, functional coupling was found in paracentral, lingual and inferior frontal areas. Paracentral connectivity strength in patients was associated with disease burden and motor symptoms. These data suggest intact cerebellar volume in preHD. In contrast, early manifest HD patients exhibit atrophy of specific cerebellar subregions and abnormal corticocerebellar functional coupling. In early HD, the association between paracentral lobule function and clinical parameters suggests that corticocerebellar connectivity strength is related to the evolution of HD biology and the severity of HD motor signs.

Neurological abnormalities in recent-onset schizophrenia and asperger-syndrome.

BACKGROUND: Neurological abnormalities including a variety of subtle deficits such as discrete impairments in sensory integration, motor coordination (MOCO), and sequencing of complex motor acts are frequently found in patients with schizophrenia (SZ) and commonly referred to as neurological soft signs (NSS). Asperger-syndrome (AS) is characterized by sensory-motor difficulties as well. However, the question whether the two disorders share a common or a disease-specific pattern of NSS remains unresolved. METHOD: A total of 78 age- and education-matched participants [26 patients with recent-onset SZ, 26 individuals with AS, and 26 healthy controls (HC)] were recruited for the study. Analyses of covariance (ANCOVAs), with age, years of education, and medication included as covariates, were used to examine group differences on total NSS and the five subscale scores. Discriminant analyses were employed to identify the NSS subscales that maximally discriminate between the three groups. RESULTS: Significant differences among the three groups were found in NSS total score and on the five NSS subscales. The clinical groups differed significantly in the NSS subscale MOCO. The correct discriminant rate between patients with SZ and individuals with AS was 61.5%. The correct discriminant rate was 92.3% between individuals with AS and HC, and 80.8% between SZ patients and HC, respectively. CONCLUSION: Our findings provide new evidence for the presence of NSS in AS and lend further support to previously reported difficulties in movement control in this disorder. According to the present results, SZ and AS seem to be characterized by both quantitative and qualitative NSS expression.

Cortical signature of neurological soft signs in recent onset schizophrenia.

Motor symptoms such as neurological soft signs (NSS) are characteristic phenomena of schizophrenia at any stage of the illness. Neuroimaging studies in schizophrenia patients have shown regional thinning of the cortical mantle, but it is unknown at present whether NSS are related to cortical thickness changes. Whole brain high-resolution magnetic resonance imaging at 3 Tesla was used to investigate cortical thickness in 28 patients with recent-onset schizophrenia. Cortical reconstruction was performed with the Freesurfer image analysis suite. NSS were examined on the Heidelberg Scale and related to cortical thickness. Age, education, and medication were considered as potential confounders. Higher NSS scores were associated with morphological changes of cortical thickness in multiple areas comprising paracentral gyrus, postcentral lobule, precuneus, inferior parietal lobule and temporal lobe. Our results confirm the hypothesis of a significant relationship between cortical thickness changes and the extent of NSS in schizophrenia. Investigation of cortical thickness may help to explain subtle motor symptoms such as NSS in schizophrenia.

Longitudinal task-negative network analyses in preclinical Huntington's disease.

Functional neuroimaging studies have reported task-related brain activation changes in preclinical individuals carrying the Huntington's disease (HD) gene mutation (preHD). Little is known about "task-negative" activity, i.e., patterns of task-related deactivation in preHD, and about the stability of any deactivation changes over the course of the disease. Here, we explored task-related deactivation and functional connectivity of "task-negative" networks (TNNs) in preHD followed over a time period of 2 years. Thirteen far-from-onset preHD (mean time to estimated motor onset = 19.5 years) and thirteen healthy controls were investigated. We used functional magnetic resonance imaging (fMRI), a verbal working memory task, and uni- and multivariate analysis techniques for fMRI data. Behavior was similar in preHD and controls at baseline and did not change 2 years later. At both time points, deactivation was similar in preHD and controls. Within two spatio-temporally distinct TNNs, preHD had lower functional connectivity in the posterior cingulate cortex and higher functional connectivity in the left anterior prefrontal cortex compared to controls (p < 0.05, cluster-corrected). These findings remained stable at follow-up. Anterior prefrontal connectivity correlated with disease burden scores both at baseline and at follow-up. Over time, preHD exhibited higher connectivity in a dorsal cingulate region. Functional connectivity differences within this region were inversely associated with changes of motor function. These data provide first evidence for TNN connectivity changes in preHD followed over a period of 2 years. The relationship between dorsal cingulate connectivity and motor function suggests that "task-negative" activity may capture time-sensitive neural and functional processes in preHD.

Disturbance of intentionality: a phenomenological study of body-affecting first-rank symptoms in schizophrenia.

OBJECTIVES: In 1950, Kurt Schneider proposed that a considerable number of schizophrenia patients develop first-rank symptoms (FRS). In such cases, patients report made experiences, replaced control of will, thought insertion, broadcast or withdrawal and delusional perception, respectively. Although a number of recent studies tend to explain FRS in terms of neurobiological and neuropsychological processes, the origin of these symptoms still remains unknown. In this paper, we explore the subjective experience of patients with the following two FRS: (1) "made" impulses and (2) "made" volitional acts. METHOD: The method applied for the study of two FRS consists first in the overview of psychiatric and philosophical literature and second in the further investigation of subjective experience in patients with FRS. Psychopathological and phenomenological aspects of FRS are discussed by means of patient cases. RESULTS: We discovered a profound transformation of intentionality and agency in schizophrenia patients with body-affecting FRS. This concept offers an insight into the interrelatedness between particular FRS. CONCLUSION: We propose that the subjective experience of schizophrenia patients with body-affecting FRS is rooted in the disturbance of intentionality and diminished sense of agency. This theoretical account of body-affecting FRS will open up new directions in both phenomenological and neurobiological psychiatric research.

Neurological soft signs and brainstem morphology in first-episode schizophrenia.

BACKGROUND: Minor motor and sensory deficits or neurological soft signs (NSS) have frequently been reported in patients with schizophrenia at any stage of their illness. NSS have been demonstrated to correlate with neuroanatomical abnormalities in various brain regions. Despite its important role in the integration and coordination of automatic motor actions, the brainstem has so far rather been ignored in previous neuroimaging studies on NSS in schizophrenia. METHOD: We investigated 21 right-handed first-episode schizophrenia patients using high-resolution magnetic resonance imaging at 3 T. The severity of NSS was measured with the Heidelberg Scale. Associations between NSS and both brainstem volume and shape changes were examined. RESULTS: Higher NSS scores were significantly associated with structural alterations in the brainstem. According to volume measurements higher NSS scores correlated with global changes of the brainstem. Using shape analyses these associations referred to regionally specific morphometric alterations predominantly in the midbrain and pons. CONCLUSION: The findings suggest that brainstem morphometric alterations are associated with the severity of NSS in patients with first-episode schizophrenia. They further indicate the involvement of the brainstem in the pathogenesis of schizophrenia.

Abnormal gray and white matter volume in delusional infestation.

Little is known about the neural basis of delusional infestation (DI), the delusional belief to be infested with pathogens. Case series and the response to anti-dopaminergic medication indicate disruptions in dopaminergic neurotransmission in the striatum (caudate, putamen), but did not allow for population-based inference. Here, we report the first whole-brain structural neuroimaging study to investigate gray and white matter abnormalities in DI compared to controls. In this study, we used structural magnetic resonance imaging and voxel-based morphometry to investigate gray and white matter volume in 16 DI patients and 16 matched healthy controls. Lower gray matter volume in DI patients compared to controls was found in left medial, lateral and right superior frontal cortices, left anterior cingulate cortex, bilateral insula, left thalamus, right striatal areas and in lateral and medial temporal cortical regions (p<0.05, cluster-corrected). Higher white matter volume in DI patients compared to controls was found in right middle cingulate, left frontal opercular and bilateral striatal regions (p<0.05, cluster-corrected). This study shows that structural changes in prefrontal, temporal, insular, cingulate and striatal brain regions are associated with DI, supporting a neurobiological model of disrupted prefrontal control over somato-sensory representations.

Brain structure in preclinical Huntington's disease: a multi-method approach.

BACKGROUND: Structural magnetic resonance imaging (MRI) of the brain could be a powerful tool for discovering early biomarkers in clinically presymptomatic carriers of the Huntington's disease gene mutation (preHD). So far, structural changes have been found mainly in preHD approaching the estimated motor onset of the disease (i.e., less than 15 years from onset), whereas structural findings in preHD far from the estimated motor onset have been inconclusive. OBJECTIVES: The aims of this study were to investigate the sensitivity of different methodological approaches to structural data in far-from-onset preHD (mean estimated time to motor onset = 21.4 years) and to explore the relationship between brain structure, clinical variables and cognition. METHODS: High-resolution MRI data at 3 T were obtained from 20 preHD individuals and 20 healthy participants and subsequently analyzed using voxel-based morphometry (VBM), cortical surface modeling and subcortical segmentation analysis techniques. RESULTS: VBM analyses did not reveal significant between-group differences, whereas cortical surface modeling and subcortical segmentation analyses showed significant regional cortical thinning and striatal changes in preHD compared to controls. Significant correlations were found between striatal structure, estimated time to motor onset and executive performance, whereas cortical changes were not significantly correlated with these parameters. CONCLUSION: These data suggest that a combined methodological approach to structural MRI data could increase the sensitivity for detecting subtle neurobiological changes in early preHD. As consistently shown across different methods, the association between striatal structure and clinical measures supports the notion that changes in striatal volume could represent a more robust marker of disease progression than cortical changes.

Hippocampal volume reduction and autobiographical memory deficits in chronic schizophrenia.

Although autobiographical memory (AM) deficits and hippocampal changes are frequently found in schizophrenia, their actual association remained yet to be established. AM performance and hippocampal volume were examined in 33 older, chronic schizophrenic patients and 21 healthy volunteers matched for age, gender and education. Psychopathological symptoms and additional neuropsychological parameters were assessed by using appropriate rating scales; magnetic resonance imaging (MRI) 3-T data were analyzed via an automated region-of-interest procedure. When compared with the control subjects, patients showed significantly decreased left anterior and posterior hippocampal volumes. Episodic but not semantic AM performance was significantly lower in the patients than in the healthy controls. Both episodic and semantic AM deficits were significantly correlated with volume of the left hippocampus in the patient group. In contrast, deficits in verbal memory, working memory and remote semantic memory observed in the patients did not relate to hippocampal volume. Our findings indicate that AM deficits in chronic schizophrenia are associated with hippocampal volume reductions and underline the importance of this pathology in schizophrenia.

Hippocampal and entorhinal cortex volume decline in cognitively intact elderly.

Studying the distribution and chronological sequence of brain morphological changes that occur in normal aging is crucial for understanding the mechanisms underlying these alterations and for distinguishing them from pathological processes. Whether the hippocampal formation is subjected to or spared from age-related shrinkage still remains controversial. We used magnetic resonance imaging (MRI) in order to assess hippocampal and entorhinal morphology in two population-based cognitively unimpaired cohorts (aged 53-55 years and 73-75 years, respectively) matched for gender, education, handedness, and apolipoprotein E status. Voxel-based morphometry (VBM-DARTEL) and shape analysis (FSL-FIRST) revealed significant bihemispheric age-related shrinkage of subiculum and cornu ammonis as well as of the entorhinal cortex (investigated with VBM only). The results lend further support to an effect of aging on medial temporal lobe morphology and thus may be of importance for the interpretation of structural imaging findings, especially in those diseases that are typically related to advancing age, as well as for the interpretation of functional imaging studies, where age-related differences in hippocampal activation may--to a locally varying degree--be explained by morphometric alterations.

Brain activation and functional connectivity in premanifest Huntington's disease during states of intrinsic and phasic alertness.

Previous functional neuroimaging studies have shown brain activation abnormalities in clinically presymptomatic carriers of the Huntington's disease (preHD) gene mutation when performing complex cognitive tasks. However, little is known about the neural correlates of attentional processes in preHD. In this study, we used functional magnetic resonance imaging to investigate basic aspects of attentional processing in preHD individuals (n = 18) compared to healthy participants (n = 18) during an alertness task. Uni- and multivariate statistical techniques were used to assess task-related regional brain activation and functional network connectivity. Compared to healthy controls, preHD individuals near to the estimated onset of clinical signs showed lower activation of right frontostriatal regions during phasic alertness (P < 0.001, uncorrected). Decreased striatal activation in this preHD subgroup was also evident when compared with those preHD individuals far from the estimated onset of HD signs. Lower putaminal activity was associated with longer reaction times and with proximity to onset. In addition, preHD participants near to onset had lower functional connectivity of motor regions when compared with controls and preHD individuals far from onset. Our data suggest that while alertness-related performance remains normal, the underlying frontostriatal activity and motor cortex connectivity decline only when approaching the onset of unequivocal signs of HD. However, these attentional network changes might not be the sole explanation for the differences in cognitive task performance previously observed in preHD.