Tonic and Phasic Alertness Training: A Novel Behavioral Therapy to Improve Spatial and Non-Spatial Attention in Patients with Hemispatial Neglect

Hemispatial neglect is a debilitating disorder marked by a constellation of spatial and non-spatial attention deficits. Patients’ alertness deficits have shown to interact with lateralized attention processes and correspondingly, improving tonic/general alertness as well as phasic/moment-to-moment alertness has shown to ameliorate spatial bias. However, improvements are often short-lived and inconsistent across tasks and patients. In an attempt to more effectively activate alertness mechanisms by exercising both tonic and phasic alertness, we employed a novel version of a continuous performance task (tonic and phasic alertness training, TAPAT). Using a between-subjects longitudinal design and employing sensitive outcome measures of spatial and non-spatial attention, we compared the effects of 9 days of TAPAT (36 min/day) in a group of patients with chronic neglect (N = 12) with a control group of chronic neglect patients (N = 12) who simply waited during the same training period. Compared to the control group, the group trained on TAPAT significantly improved on both spatial and non-spatial measures of attention with many patients failing to exhibit a lateralized attention bias at the end of training. TAPAT was effective for patients with a range of behavioral profiles and lesions, suggesting that its effectiveness may rely on distributed or lower-level attention mechanisms that are largely intact in patients with neglect. In a follow-up experiment, to determine if TAPAT is more effective in improving spatial attention than an active treatment that directly trains spatial attention, we trained three chronic neglect patients on both TAPAT and search training. In all three patients, TAPAT training was more effective in improving spatial attention than search training suggesting that, in chronic neglect, training alertness is a more effective treatment approach than directly training spatial attention

The association between implicit and explicit affective inhibitory control, rumination and depressive symptoms

Inhibitory control underlies one’s ability to maintain goal-directed behavior by inhibiting prepotent responses or ignoring irrelevant information. Recent models suggest that impaired inhibition of negative information may contribute to depressive symptoms, and that this association is mediated by rumination. However, the exact nature of this association, particularly in non-clinical samples, is unclear. The current study assessed the relationship between inhibitory control over emotional vs. non-emotional information, rumination and depressive symptoms. A non-clinical sample of 119 participants (mean age: 36.44 ± 11.74) with various levels of depressive symptoms completed three variations of a Go/No-Go task online; two of the task variations required either explicit or implicit processing of emotional expressions, and a third variation contained no emotional expressions (i.e., neutral condition). We found reductions in inhibitory control for participants reporting elevated symptoms of depression on all three task variations, relative to less depressed participants. However, for the task variation that required implicit emotion processing, depressive symptoms were associated with inhibitory deficits for sad and neutral, but not for happy expressions. An exploratory analysis showed that the relationship between inhibition and depressive symptoms occurs in part through trait rumination for all three tasks, regardless of emotional content. Collectively, these results indicate that elevated depressive symptoms are associated with both a general inhibitory control deficit, as well as affective interference from negative emotions, with implications for the assessment and treatment of mood disorders

Shifting attention in viewer- and object-based reference frames after unilateral brain injury

The aims of the present study were to investigate the respective roles that object- and viewer-based reference frames play in reorienting visual attention, and to assess their influence after unilateral brain injury. To do so, we studied 16 right hemisphere injured (RHI) and 13 left hemisphere injured (LHI) patients. We used a cueing design that manipulates the location of cues and targets relative to a display comprised of two rectangles (i.e., objects). Unlike previous studies with patients, we presented all cues at midline rather than in the left or right visual fields. Thus, in the critical conditions in which targets were presented laterally, reorienting of attention was always from a midline cue. Performance was measured for lateralized target detection as a function of viewer-based (contra- and ipsilesional sides) and object-based (requiring reorienting within or between objects) reference frames. As expected, contralesional detection was slower than ipsilesional detection for the patients. More importantly, objects influenced target detection differently in the contralesional and ipsilesional fields. Contralesionally, reorienting to a target within the cued object took longer than reorienting to a target in the same location but in the uncued object. This finding is consistent with object-based neglect. Ipsilesionally, the means were in the opposite direction. Furthermore, no significant difference was found in object-based influences between the patient groups (RHI vs. LHI). These findings are discussed in the context of reference frames used in reorienting attention for target detection

Cardiac fibrosis in aging mice

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.The authors thank Jesse Hammer and Josiah Raddar for technical assistance. Research reported in this publication was supported by the Ellison Medical Foundation, Parker B. Francis Foundation, and the National Institutes of Health (R01AR055225 and K01AR064766). Mouse colonies were supported by the National Institutes of Health under Award Number AG025707 for the Jackson Aging Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00335-016-9634-

Therapeutic effects of apomorphine on neglect following unilateral destruction of the medial agranular cortex

Includes bibliographical references (pages [110]-118)In approximately 40% of all cases of right hemisphere stroke, patients experience a complex array of debilitating neurological deficits known as the neglect syndrome. This devastating and crippling condition is characterized by impairments in spatial and attentional processing, lack of affect, and unresponsiveness to the side of space opposite the brain lesion. Even following significant recovery, one of the major symptoms of neglect, extinction to bilateral simultaneous stimulation (extinction), often remains. Currently, there are no effective generalizable treatments of any kind for patients with neglect. A rat model of the neglect syndrome that demonstrates dramatic behavioral, anatomical, and pharmacological similarities to the human has been developed to investigate behavioral recovery of function from neglect. Studies utilizing the rodent model suggest that recovery from neglect may be due to plastic changes occurring in one area of the brain, the dorsal central striatum (DCS). Given the apparent role of the DCS in neglect and recovery from neglect, two important issues arise: is the DCS the site of drug action in studies that demonstrate acute behavioral recovery following systemic injection of the dopamine agonist apomorphine, and is the DCS involved in extinction, the most persistent symptom of neglect? Results from the current study demonstrate that direct infusion of apomorphine into the DCS, but not a more lateral striatal control area, was effective in producing acute behavioral recovery from neglect. This finding represents an important step in the development of dopamine agonist therapy in the treatment of humans with neglect. With regard to the second issue, prior to the current study, the importance of the DCS in extinction had not been investigated. Further, it was also unknown whether extinction was simply a less severe form of neglect or a unique behavioral phenomenon separate unto itself. Results from the current study demonstrate that DCS-lesioned animals, despite exhibiting neglect, do not exhibit extinction. This finding suggests that neglect and extinction are dissociable and do not share the same neural substrates. These findings are particularly important for the development of therapeutic interventions, suggesting that neural substrates other than those involved in neglect should be investigated.Ph.D. (Doctor of Philosophy

Effects of selective destruction of the dorsal central striatum on directed attention in rats

Includes bibliographical references (pages [43]-48)The neglect syndrome is a complex and devastating disorder characterized by spatial and attentional deficits, lack of affect, and unresponsiveness to the side of space opposite a brain lesion. A rodent model of neglect has been developed in order to examine the neural mechanisms underlying neglect. Unilateral destruction of the medial agranular cortex (AGm), which projects into the dorsocentral and dorsolateral striatum, produces severe neglect. A number of studies have found changes in striatum that are correlated with behavioral recovery from neglect. Physiological studies have indicated that neglect induced by AGm destruction is correlated with reductions of metabolic activity in the dorsolateral quadrant of striatum, which includes the dorsal central striatum. Further, spontaneous recovery is associated with normalization of metabolic activity in the dorsal central striatum. In addition, asymmetries in striatal immediate early gene expression have been correlated with neglect induced by AGm destruction. The present study directly tested these correlational findings by examining the behavioral effects of unilateral destruction of the dorsocentral striatum. The objective of the present study was to determine the importance of the dorsocentral striatum in the system for directed attention in the rat. Three experimental groups were used: a dorsocentral striatum NMDA lesion group, a ventral lateral striatum NMDA lesion group, and a dorsocentral striatum vehicle group. Subjects were tested for neglect 2 days post-lesion and three times per week for the following three weeks. The results showed that the dorsocentral striatum lesion group demonstrated more severe neglect than the ventral lateral striatum lesion and saline control groups. The results of the present study suggest that the dorsocentral striatum is an important component of a corticosubcortical network involved in neglect and directed attention.M.A. (Master of Arts