Impaired and preserved aspects of feedback learning in aMCI: contributions of structural connectivity.

Distinct lines of research demonstrated that patients with amnestic mild cognitive impairment (aMCI), a potential precursor of Alzheimer disease (AD), are particularly impaired in remembering relations between items and that the use of emotional targets can facilitate memory in patients with AD. We link these findings by examining learning through positive and negative feedback in patients with aMCI, and explore its anatomic underpinnings with diffusion tensor imaging and tractography. Compared to healthy controls, patients with single-domain aMCI were impaired in learning from positive feedback, while learning from negative outcomes was preserved. Among pathways within the brain circuit involved in feedback learning, abnormal white matter microstructure was observed in tracts, which connect left-hemispheric amygdala with hippocampus and entorhinal cortex. In all participants, reduced white matter integrity in this left fiber tract was specifically associated with learning from positive outcomes. Microstructure of right-hemispheric tracts between amygdala and entorhinal cortex was related to learning from negative feedback, and was not compromised in aMCI patients. Our results provide new insight into how anatomical connections might contribute to impaired and preserved aspects of learning behaviors in the early AD process and indicate potential compensatory mechanisms.

Using Voxel-Based Morphometry to Examine the Relationship between Regional Brain Volumes and Memory Performance in Amnestic Mild Cognitive Impairment.

Alzheimer's disease (AD) is a slowly progressive neurodegenerative disorder, in which morphological alterations of brain tissue develop many years before the first neuropsychological and clinical changes occur. Among the first and most prominent symptoms are deficiencies of declarative memory functions. This stage of precursory symptoms to AD has been described as amnestic mild cognitive impairment (aMCI) and is discussed as a potential AD prodrome. As therapy in the later stages of AD has been shown to be of limited impact, aMCI would be the key target for early intervention. For that purpose a comprehensive neuropsychological and anatomical characterization of this group is necessary. Previous neuropsychological investigations identified tests which are highly sensitive in diagnosing aMCI and very early AD. However, the sensitivity of those neuropsychological tests to the particular structural neuropathology in aMCI remains to be specified. To this end, we investigated 25 patients with single-domain aMCI. All participants underwent extensive neuropsychological testing and anatomical scanning with structural magnetic resonance imaging. Voxel-based morphometry (VBM) was performed to identify brain regions that show a significant correlation between regional brain volume and behavioral measures of memory and executive functioning. We found that performance in a variety of mnemonic tests was directly related to the integrity of the medial temporal lobe cortex (MTLC). Moreover, impairment of memory sub-functions in aMCI might be detected earlier than overt structural damage. By this, these findings contribute to the identification of cerebral structures associated with memory deficits in aMCI.

Impaired anatomical connectivity and related executive functions: differentiating vulnerability and disease marker in bipolar disorder.

BACKGROUND: Bipolar 1 disorder (BD1) has been associated with impaired set shifting, increased risk taking, and impaired integrity of frontolimbic white matter. However, it remains unknown to what extent these findings are related to each other and whether these abnormalities represent risk factors or consequences of the illness. METHODS: We addressed the first question by comparing 19 patients with BD1 and 19 healthy control subjects (sample 1) with diffusion tensor imaging, the Intra-Extra Dimensional Set Shift Task, and the Cambridge Gambling Task. The second question we approached by applying the same protocol to 22 healthy first-degree relatives of patients with BD1 and 22 persons without a family history of mental disorders (sample 2). RESULTS: In comparison with their control groups, BD1 patients and healthy first-degree relatives of patients with BD1 showed significantly reduced fractional anisotropy (FA) in the right anterior limb of the internal capsule and right uncinate fasciculus. White matter integrity in corpus callosum was reduced in BD1 patients only. In addition, reduced FA in anterior limb of the internal capsule correlated significantly with an increased number of errors during set shifting and increased risk taking and reduced FA in uncinate fasciculus correlated significantly with increased risk taking. CONCLUSIONS: Similar white matter alterations in BD1 patients and healthy relatives of BD1 patients are associated with comparable behavioral abnormalities. Further, results indicate that altered frontolimbic and frontothalamic connectivity and corresponding behavioral abnormalities might be a trait and vulnerability marker of BD1, whereas interhemispheric connectivity appears to be a disease marker.

Microstructure of a three-way anatomical network predicts individual differences in response inhibition: a tractography study.

Response inhibition is thought to depend critically on the inferior frontal gyrus, pars opercularis (IFGoper), presupplementary motor area (preSMA) and basal ganglia, including the subthalamic nucleus (STN), but the differential contribution of structural connections within this network to response inhibition remains unclear. Using diffusion tensor imaging and probabilistic fiber tractography, we investigated the relative associations between local white matter microstructure and stop-signal response inhibition in fronto-basal ganglia tracts delineated by probabilistic tractography. In a tract-of-interest approach, we identify significant associations with fractional anisotropy (FA) in fibers connecting the right STN region to both preSMA/SMA and IFGoper and in bilateral tracts connecting preSMA/SMA to IFGoper and the striatum. In addition, significant associations with radial diffusivity (RD) were found in fibers connecting the right preSMA/SMA to striatum and in bilateral tracts between IFGoper and STN region. In our whole-brain analysis, additional significant clusters were identified in the corpus callosum, optic radiation, inferior fronto-occipital tract and white matter of the precentral gyrus. To investigate the relative importance of regional white matter characteristics to response inhibition performance, we performed a step-wise multiple regression analysis that yielded FA in tracts connecting preSMA/SMA to the STN region and striatum, respectively, and RD in fibers connecting IFGoper to the STN region as best predictors of response inhibition performance (42% explained variance). These findings point to a specific contribution of white matter pathways connecting distinct basal ganglia structures with both medial frontal and ventrolateral prefrontal regions to response inhibition.

Genome-wide supported risk variant for bipolar disorder alters anatomical connectivity in the human brain.

Bipolar disorder is a devastating, highly heritable mental disorder related to disturbed connectivity between limbic and frontal brain areas. A meta-analysis of genome-wide association studies as well as independent replications showed ankyrin 3 (ANK3) to be one of the best-supported risk genes for bipolar disorder. Using an imaging genetics approach employing diffusion tensor imaging in 88 healthy volunteers, we show decreased white matter integrity, indicated by lower fractional anisotropy and longitudinal diffusivity, in healthy carriers of the ANK3 rs10994336 risk genotype in the anterior limb of the internal capsule. We are also able to show that the resulting alterations of cortical-striatal-thalamic circuits are related to impaired set-shifting and increased risk-taking. For risk-allele carriers of ANK3 rs9804190 no white matter alterations or neuropsychological impairments were observed. In sum, our findings show that ANK3 rs10994336 or a variant in linkage-disequilibrium is functional in the human brain and also influences behavioral phenotypes related to bipolar disorder.

Loss of callosal fibre integrity in healthy elderly with age-related white matter changes.

Age-related white matter changes (ARWMC) appear to correspond to a continuum from normal functioning to clinically overt neurological syndromes. Disturbance of the structural integrity of cerebral fibre tracts-the so-called cerebral network-by ARWMC might be one explanation for this development. From 3 T magnetic resonance imaging (MRI) data of 34 healthy elderly subjects (60-82 years) we calculated the lesion volume of ARWMC and the area of the corpus callosum (CC). Gait, balance and cognition were assessed. We compared these findings in those with mild (n = 22) and advanced (n = 12) ARWMC and performed tract-based spatial statistics (TBSS) to analyze white matter structural integrity. In subjects with advanced ARWMC, TBSS showed a significant decrease of fractional anisotropy (FA) in several large tracts of the white matter including the CC; total CC, CC2 and CC5 areas were significantly smaller. Despite these morphological changes, tests of gait, balance and cognition as measured by the Mini-Mental State Examination (MMSE) were in the normal range for both groups; only the Montreal Cognitive Assessment (MoCA) detected executive and language dysfunction in those with advanced ARWMC. Loss of tissue integrity and atrophy of the CC secondary to spatially remote lesions in the peri- and paraventricular white matter in ARWMC appear to be already detectable in healthy elderly individuals.

Motivational orientation modulates the neural response to reward.

Motivational orientation defines the source of motivation for an individual to perform a particular action and can either originate from internal desires (e.g., interest) or external compensation (e.g., money). To this end, motivational orientation should influence the way positive or negative feedback is processed during learning situations and this might in turn have an impact on the learning process. In the present study, we thus investigated whether motivational orientation, i.e., extrinsic and intrinsic motivation modulates the neural response to reward and punishment as well as learning from reward and punishment in 33 healthy individuals. To assess neural responses to reward, punishment and learning of reward contingencies we employed a probabilistic reversal learning task during functional magnetic resonance imaging. Extrinsic and intrinsic motivation were assessed with a self-report questionnaire. Rewarding trials fostered activation in the medial orbitofrontal cortex and anterior cingulate gyrus (ACC) as well as the amygdala and nucleus accumbens, whereas for punishment an increased neural response was observed in the medial and inferior prefrontal cortex, the superior parietal cortex and the insula. High extrinsic motivation was positively correlated to increased neural responses to reward in the ACC, amygdala and putamen, whereas a negative relationship between intrinsic motivation and brain activation in these brain regions was observed. These findings show that motivational orientation indeed modulates the responsiveness to reward delivery in major components of the human reward system and therefore extends previous results showing a significant influence of individual differences in reward-related personality traits on the neural processing of reward.