Investigation of Brain Iron in Niemann-Pick Type C: A 7T Quantitative Susceptibility Mapping Study.

BACKGROUND AND PURPOSE: While brain iron dysregulation has been observed in several neurodegenerative disorders, its association with the progressive neurodegeneration in Niemann-Pick type C is unknown. Systemic iron abnormalities have been reported in patients with Niemann-Pick type C and in animal models of Niemann-Pick type C. In this study, we examined brain iron using quantitative susceptibility mapping MR imaging in individuals with Niemann-Pick type C compared with healthy controls. MATERIALS AND METHODS: A cohort of 10 patients with adolescent- and adult-onset Niemann-Pick type C and 14 age- and sex-matched healthy controls underwent 7T brain MR imaging with T1 and quantitative susceptibility mapping acquisitions. A probing whole-brain voxelwise comparison of quantitative susceptibility mapping between groups was conducted. Mean quantitative susceptibility mapping in the ROIs (thalamus, hippocampus, putamen, caudate nucleus, and globus pallidus) was further compared. The correlations between regional volume, quantitative susceptibility mapping values, and clinical features, which included disease severity on the Iturriaga scale, cognitive function, and the Social and Occupational Functioning Assessment Scale, were explored as secondary analyses. RESULTS: We observed lower volume in the thalamus and voxel clusters of higher quantitative susceptibility mapping in the pulvinar nuclei bilaterally in patients with Niemann-Pick type C compared with the control group. In patients with Niemann-Pick type C, higher quantitative susceptibility mapping in the pulvinar nucleus clusters correlated with lower volume of the thalamus on both sides. Moreover, higher quantitative susceptibility mapping in the right pulvinar cluster was associated with greater disease severity. CONCLUSIONS: Our findings suggest iron deposition in the pulvinar nucleus in Niemann-Pick type C disease, which is associated with thalamic atrophy and disease severity. This preliminary evidence supports the link between iron and neurodegeneration in Niemann-Pick type C, in line with existing literature on other neurodegenerative disorders.

The enduring effect of prenatal protein malnutrition on brain anatomy, physiology and behavior.

There is increasing evidence that the maternal environment exerts enduring influences on the fetal brain. In response to certain environmental stimuli such as reduced protein content, the fetus changes the course of its brain development, which leads to specific and programed changes in brain anatomy and physiology. These alterations produce a brain with a fundamentally altered organization, which then translates to alterations in adult cognitive function. The effects on brain and behavior may be linked, such that a prenatal stimulus relays a signal to alter brain development and encourage the selection and development of brain circuits and behaviors that would be beneficial for the environment in which the animal was anticipated to emerge. At the same time, the signal would deselect behaviors unlikely to be adaptive. We draw on evidence from rodent models to suggest that the brain that develops after a reduction in protein during the prenatal phase is not uniformly dysfunctional, but simply different. This perspective has implications for the role of prenatal factors in the production and expression of behavior, and may account for the elevation of risk factors for neurological and psychiatric illnesses.

The neural basis of attentional alterations in prenatally protein malnourished rats.

Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predictor of task performance in controls but not prenatally malnourished animals. Instead, prenatally malnourished animals relied on different brain networks involving limbic structures such as the hippocampus. These results provide evidence that protein reduction during brain development has more wide-reaching effects on brain networks than previously appreciated, resulting in the formation of brain networks that may reflect compensatory responses in prenatally malnourished brains.

Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex.

Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity.

Multiple sessions of transcranial direct current stimulation to the intact hemisphere improves visual function after unilateral ablation of visual cortex.

Damage to cerebral systems is frequently followed by the emergence of compensatory mechanisms, which serve to reduce the effects of brain damage and allow recovery of function. Intrinsic recovery, however, is rarely complete. Non-invasive brain stimulation technologies have the potential to actively shape neural circuits and enhance recovery from brain damage. In this study, a stable deficit for detecting and orienting to visual stimuli presented in the contralesional visual hemifield was generated by producing unilateral brain damage of the right posterior parietal and contiguous visual cortical areas. A long regimen of inhibitory non-invasive transcranial direct-current stimulation (cathodal tDCS, 2 mA, 20 min) was applied to the contralateral (intact) posterior parietal cortex over 14 weeks (total of 70 sessions, one per day, 5 days per week) and behavioral outcomes were periodically assessed. In three out of four stimulated cats, lasting recovery of visuospatial function was observed. Recovery started after 2-3 weeks of stimulation, and recovered targets were located first in the periphery, and moved to more central visual field locations with the accrual of stimulation sessions. Recovery for moving tasks followed a biphasic pattern before reaching plateau levels. Recovery did not occur for more difficult visual tasks. These findings highlight the ability of multiple sessions of transcranial direct-current stimulation to produce recovery of visuospatial function after unilateral brain damage.

Recovery of function following unilateral damage to visuoparietal cortex.

Damage to the visuoparietal cortex located in the banks of the middle suprasylvian gyrus of the cat has been shown to produce a deficit in the detection and localization of moving visual cues presented in the contralesional visual hemifield. There is evidence from reversible cooling deactivation studies that the integrity of this orienting function is not completely dependent on the VP cortex and that under the right circumstances, other brain regions may come online and completely take over the processing that subserves this behavior. We examined the recovery of orienting behavior after unilateral damage to the VP cortex. We found that consistent with previous data, VP damage produced an impairment in the capacity to detect and orient to moving visual stimuli in the contralesional visual field. Over a span of days, spontaneous recovery fully occurred. The ability to detect and localize static visual stimuli was tested as a fiducial measure of parietal cortex function, and this function did not recover. We conclude that the detection and localization of moving visual stimuli is not a function that requires VP cortex and argue for the existence of a parallel and redundant subcortical-cortical brain network that serves as the substrate for recovery of function.

A novel approach for documenting phosphenes induced by transcranial magnetic stimulation.

Stimulation of the human visual cortex produces a transient perception of light, known as a phosphene. Phosphenes are induced by invasive electrical stimulation of the occipital cortex, but also by non-invasive Transcranial Magnetic Stimulation (TMS)(1) of the same cortical regions. The intensity at which a phosphene is induced (phosphene threshold) is a well established measure of visual cortical excitability and is used to study cortico-cortical interactions, functional organization (2), susceptibility to pathology (3,4) and visual processing (5-7). Phosphenes are typically defined by three characteristics: they are observed in the visual hemifield contralateral to stimulation; they are induced when the subject s eyes are open or closed, and their spatial location changes with the direction of gaze (2). Various methods have been used to document phosphenes, but a standardized methodology is lacking. We demonstrate a reliable procedure to obtain phosphene threshold values and introduce a novel system for the documentation and analysis of phosphenes. We developed the Laser Tracking and Painting system (LTaP), a low cost, easily built and operated system that records the location and size of perceived phosphenes in real-time. The LTaP system provides a stable and customizable environment for quantification and analysis of phosphenes.

Cathodal transcranial direct current stimulation on posterior parietal cortex disrupts visuo-spatial processing in the contralateral visual field.

Transcranial direct current stimulation (tDCS) has recently undergone a resurgence in popularity as a powerful tool to non-invasively manipulate brain activity. While tDCS has been used to alter functions tied to primary motor and visual cortices, its impact on extrastriate visual areas involved in visuo-spatial processing has not yet been examined. In the current study, we applied tDCS to the cat visuoparietal (VP) cortex and assayed performance in a paradigm designed to assess the capacity to detect, localize and orient to static targets appearing at different spatial eccentricities within the visual field. Real or sham cathodal tDCS was unilaterally applied to the VP cortex, and orienting performance was assessed during (online), immediately after (offline; Experiments 1 and 2), and 1 or 24 h after the end of the tDCS stimulation (Experiment 2). Performance was compared to baseline data collected immediately prior to stimulation. Real, but not sham, tDCS induced significant decreases in performance for static visual targets presented in the contrastimulated visual hemifield. The behavioral impact of tDCS was most apparent during the online and immediate offline periods. The tDCS effect decayed progressively over time and performance returned to baseline levels approximately 60 min after stimulation. These results are consistent with the effects of both invasive and non-invasive deactivation methods applied to the same brain region, and indicate that tDCS has the potential to modify neuronal activity in extrastriate visual regions and to sculpt brain activity and behavior in normal and neurologically impaired subjects.

Low frequency transcranial magnetic stimulation on the posterior parietal cortex induces visuotopically specific neglect-like syndrome.

The visuo-parietal (VP) region of the cerebral cortex is critically involved in the generation of orienting responses towards visual stimuli. In this study we use repetitive transcranial magnetic stimulation (rTMS) to unilaterally and non-invasively deactivate the VP cortex during a simple spatial visual detection task tested in real space. Adult cats were intensively trained over 4 months on a task requiring them to detect and orient to a peripheral punctuate static LED presented at a peripheral location between 0 degrees and 90 degrees , to the right or left of a 0 degrees fixation target. In 16 different interleaved sessions, real or sham low frequency (1 Hz) rTMS was unilaterally applied during 20 min (1,200 pulses) to the VP cortex. The percentage of mistakes detecting and orienting to contralateral visual targets increased significantly during the 15-20 min immediately following real but not sham rTMS. Behavioral deficits were most marked in peripheral eccentricities, whereas more central locations were largely unaffected. Performance returned to baseline (pre-TMS) levels when animals were tested 45 min later and remained in pre-TMS levels 24 h after the end of the stimulation. Our results confirm that the VP cortex of the cat is critical for successful detection and orienting to visual stimuli presented in the corresponding contralateral visual field. In addition, we show that rTMS disrupts a robust behavioral task known to depend on VP cortex and does so for the far periphery of the visual field, but not for more central targets.

Neonatal isolation alters LTP in freely moving juvenile rats: sex differences.

We have previously reported that neonatal isolation significantly enhanced the magnitude of hippocampal long-term potentiation (LTP) recorded from freely moving male rats tested at 30 days of age. The present study extends this work to examine the effects of neonatal isolation on hippocampal LTP in male and female juvenile rats. Changes in dentate granule cell population measures, i.e., EPSP slope and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway were used to assess the effects of neonatal isolation on LTP over a period of 96 hrs. Prior to tetanization, significant sex differences were obtained for input/output (I/O) response measures of EPSP slope and PSA, with males showing consistently higher values than females. No significant effect of treatment was obtained within either sex for baseline measures. Following tetanization significant sex differences were also obtained for both measures, with males showing significantly greater enhancement than females. Comparisons made at 1 hr post-tetanization (establishment of LTP) indicated that isolated males showed significantly greater enhancement than any other group. On the other hand, treatment differences were not obtained from females. At 96 hrs (maintenance of LTP), however, both neonatally isolated males and females showed significantly greater enhancement than either non-isolated siblings or unhandled controls. These results indicate that males and females exhibit different enhancement profiles with respect to both the magnitude and duration of LTP, and that neonatal isolation alters these profiles in a sex-specific manner.