Effects of Transcranial Direct Current Stimulation on Baseline and Slope of Prefrontal Cortex Hemodynamics During a Spatial Working Memory Task.

Background: Transcranial direct current stimulation (tDCS) has been shown to be an inexpensive, safe, and effective way of augmenting a variety of cognitive abilities. Relatively recent advances in neuroimaging technology have provided the ability to measure brain activity concurrently during active brain stimulation rather than after stimulation. The effects on brain activity elicited by tDCS during active tDCS reported by initial studies have been somewhat conflicted and seemingly dependent on whether a behavioral improvement was observed. Objective: The current study set out to address questions regarding behavioral change, within and between-participant designs as well as differentiating the effects on hemodynamic amplitude and baseline during active tDCS stimulation. Methods: We tested the effects of transcranial direct current stimulation (tDCS) on anterior hemodynamics in prefrontal cortex during performance on a spatial memory task. Prefrontal cortex activity was measured with functional near infrared spectroscopy (fNIRS), a wearable and portable neuroimaging technique that utilizes near infrared light to measure cortical oxygenated and deoxygenated hemoglobin changes non-invasively. There were two groups, one group (n = 10) received only sham stimulation and the other group (n = 11) received sham followed by anodal stimulation to right ventral lateral prefrontal cortex. Results: Analyses revealed an increase in spatial memory performance following tDCS stimulation. This augmented performance was accompanied by changes to oxygenation (HbO-HbR) at the onset of the hemodynamic response in bilateral dorsolateral prefrontal cortex and left ventral medial prefrontal cortex. In these regions we also observed that stimulation improved neural processing efficiency, by reducing oxygenation and increasing performance from block to block. During and following tDCS stimulation, it was also observed that in bilateral dorsolateral prefrontal cortex the relationship between performance and oxygenation inverted, from a negative relationship to a positive relationship. Conclusion: The results suggest that tDCS is predominately a mechanism for changing neurons propensity for activity as opposed to their strength of activity. tDCS not only alters the efficiency of task relevant processing, but also the nature in which hemodynamic resources are used during augmented task performance.

Hypothesis for cognitive effects of transcranial direct current stimulation: Externally- and internally-directed cognition.

A comprehensive explanation is lacking for the broad array of cognitive effects modulated by transcranial direct current stimulation (tDCS). We advanced the testable hypothesis that tDCS to the default mode network (DMN) increases processing of goals and stored information at the expense of external events. We further hypothesized that tDCS to the dorsal attention network (DAN) increases processing of external events at the expense of goals and stored information. A literature search (PsychINFO) identified 42 empirical studies and 3 meta-analyses examining effects of prefrontal and/or parietal tDCS on tasks that selectively required external and/or internal processing. Most, though not all, of the studies that met our search criteria supported our hypothesis. Three meta-analyses supported our hypothesis. The hypothesis we advanced provides a framework for the design and interpretation of results in light of the role of large-scale intrinsic networks that govern attention.

Prefrontal Hemodynamics of Physical Activity and Environmental Complexity During Cognitive Work.

OBJECTIVE: The aim of this study was to assess performance and cognitive states during cognitive work in the presence of physical work and in natural settings. BACKGROUND: Authors of previous studies have examined the interaction between cognitive and physical work, finding performance decrements in working memory. Neuroimaging has revealed increases and decreases in prefrontal oxygenated hemoglobin during the interaction of cognitive and physical work. The effect of environment on cognitive-physical dual tasking has not been previously considered. METHOD: Thirteen participants were monitored with wireless functional near-infrared spectroscopy (fNIRS) as they performed an auditory 1-back task while sitting, walking indoors, and walking outdoors. RESULTS: Relative to sitting and walking indoors, auditory working memory performance declined when participants were walking outdoors. Sitting during the auditory 1-back task increased oxygenated hemoglobin and decreased deoxygenated hemoglobin in bilateral prefrontal cortex. Walking reduced the total hemoglobin available to bilateral prefrontal cortex. An increase in environmental complexity reduced oxygenated hemoglobin and increased deoxygenated hemoglobin in bilateral prefrontal cortex. CONCLUSION: Wireless fNIRS is capable of monitoring cognitive states in naturalistic environments. Selective attention and physical work compete with executive processing. During executive processing loading of selective attention and physical work results in deactivation of bilateral prefrontal cortex and degraded working memory performance, indicating that physical work and concomitant selective attention may supersede executive processing in the distribution of mental resources. APPLICATION: This research informs decision-making procedures in work where working memory, physical activity, and attention interact. Where working memory is paramount, precautions should be taken to eliminate competition from physical work and selective attention.

Reducing the Disruptive Effects of Interruptions With Noninvasive Brain Stimulation.

OBJECTIVE: The authors determine whether transcranial direct current stimulation (tDCS) can reduce resumption time when an ongoing task is interrupted. BACKGROUND: Interruptions are common and disruptive. Working memory capacity has been shown to predict resumption lag (i.e., time to successfully resume a task after interruption). Given that tDCS applied to brain areas associated with working memory can enhance performance, tDCS has the potential to improve resumption lag when a task is interrupted. METHOD: Participants were randomly assigned to one of four groups that received anodal (active) stimulation of 2 mA tDCS to one of two target brain regions, left and right dorsolateral prefrontal cortex (DLPFC), or to one of two control areas, active stimulation of the left primary motor cortex or sham stimulation of the right DLPFC, while completing a financial management task that was intermittently interrupted with math problem solving. RESULTS: Anodal stimulation to the right and left DLPFC significantly reduced resumption lags compared to the control conditions (sham and left motor cortex stimulation). Additionally, there was no speed-accuracy tradeoff (i.e., the improvement in resumption time was not accompanied by an increased error rate). CONCLUSION: Noninvasive brain stimulation can significantly decrease resumption lag (improve performance) after a task is interrupted. APPLICATION: Noninvasive brain stimulation offers an easy-to-apply tool that can significantly improve interrupted task performance.

Transcranial direct current stimulation facilitates cognitive multi-task performance differentially depending on anode location and subtask.

There is a need to facilitate acquisition of real world cognitive multi-tasks that require long periods of training (e.g., air traffic control, intelligence analysis, medicine). Non-invasive brain stimulation-specifically transcranial Direct Current Stimulation (tDCS)-has promise as a method to speed multi-task training. We hypothesized that during acquisition of the complex multi-task Space Fortress, subtasks that require focused attention on ship control would benefit from tDCS aimed at the dorsal attention network while subtasks that require redirection of attention would benefit from tDCS aimed at the right hemisphere ventral attention network. We compared effects of 30 min prefrontal and parietal stimulation to right and left hemispheres on subtask performance during the first 45 min of training. The strongest effects both overall and for ship flying (control and velocity subtasks) were seen with a right parietal (C4, reference to left shoulder) montage, shown by modeling to induce an electric field that includes nodes in both dorsal and ventral attention networks. This is consistent with the re-orienting hypothesis that the ventral attention network is activated along with the dorsal attention network if a new, task-relevant event occurs while visuospatial attention is focused (Corbetta et al., 2008). No effects were seen with anodes over sites that stimulated only dorsal (C3) or only ventral (F10) attention networks. The speed subtask (update memory for symbols) benefited from an F9 anode over left prefrontal cortex. These results argue for development of tDCS as a training aid in real world settings where multi-tasking is critical.

Prenatal influence of an androgen agonist and antagonist on the differentiation of the ovine sexually dimorphic nucleus in male and female lamb fetuses.

The ovine sexually dimorphic nucleus (oSDN) is 2 times larger in rams than in ewes. Sexual differentiation of the oSDN is produced by testosterone exposure during the critical period occurring between gestational day (GD)60 and GD90 (term, 147 d). We tested the hypothesis that testosterone acts through the androgen receptor to control development of the male-typical oSDN. In experiment 1, pregnant ewes received injections of vehicle, androgen receptor antagonist flutamide, or nonaromatizable androgen dihydrotestosterone (DHT) propionate during the critical period. Fetuses were delivered at GD135. Both antagonist and agonist treatments significantly reduced mean oSDN volume in males but had no effects in females. Experiment 2, we analyzed the effect of treatments on the fetal hypothalamic-pituitary-gonadal axis to determine whether compensatory changes in hormone secretion occurred that could explain the effect of DHT. Pregnant ewes were injected with vehicle, flutamide, or DHT propionate from GD60 to GD84, and fetuses were delivered on GD85. Flutamide significantly increased LH and testosterone in males, whereas DHT significantly decreased both hormones. In females, LH was unaffected by flutamide but significantly reduced by DHT exposure. DHT significantly decreased pituitary gonadotropin and hypothalamic kisspeptin mRNA expression in males and females. These results suggest that androgen receptor mediates the effect of testosterone on oSDN masculinization, because this process was blocked by the androgen receptor antagonist flutamide in eugonadal males. In contrast, the reduction of oSDN volume observed after DHT exposure appears to be mediated by a negative feedback mechanism exerted on the hypothalamus to reduce LH and testosterone secretion. The reduced androgen exposure most likely accounted for the decreased oSDN volume. We conclude that, during the critical period, the male reproductive axis in long gestation species, such as sheep, is sufficiently developed to react to perturbations in serum androgens and mitigate disruptions in brain masculinization.

Cell death in the central division of the medial preoptic nucleus of male and female lamb fetuses.

The medial preoptic area of the adult sheep contains an ovine sexually dimorphic nucleus (oSDN) that is larger and has more neurons in males than in females. In the lamb fetus, the nascent oSDN occupies the central division of the medial preoptic nucleus (MPNc) and consists of a cluster of cells that is organized by the action of testosterone during gestational days 60-90 of a 147 day term pregnancy. The current study sought to determine whether programmed cell death contributes to the emergence of the oSDN. Male and female lamb fetuses were euthanized at different ages spanning the period during which the oSDN is organized. The expression of the pro- and anti-apoptotic genes bcl-2 and bax, respectively, was measured by quantitative RT-PCR to assess possible sex differences in neuron vulnerability to programmed cell death. The appearance of DNA-fragmentation was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and used to estimate the occurrence of apoptotic cell death. We found that bcl-2 and bax mRNA expression in the medial preoptic area of the developing lamb fetus decreased during the last half of the 147-day gestation. The ratio of bcl-2/bax gene expression was highest at gestational day 85 but was equivalent between males and females. TUNEL staining in the MPNc was very low and although it decreased significantly with age, it was not significantly different between sexes. These results using two different methods to assess cell death indicate that a sex difference in the incidence of cell death is not a primary mechanism leading to sexual differentiation of the oSDN.

Medroxyprogesterone acetate impairs memory and alters the GABAergic system in aged surgically menopausal rats.

In women, medroxyprogesterone acetate (MPA) is the most commonly used progestin component of hormone therapy (HT). In vitro, MPA negatively impacts markers of neuronal health and exacerbates experimentally-induced neurotoxicity. There is in vitro evidence that these factors are driven by GABAergic and neurotrophic systems. Whether these effects translate to a negative impact on brain function has not been tested in vivo, clinically or preclinically. Here we evaluate the mnemonic and neurobiological effects of MPA in the surgically menopausal rat. Aged ovariectomized (OVX) rats were given subcutaneous vehicle, natural progesterone, low-dose MPA or high-dose MPA. Multiple cognitive domains were analyzed via the water radial-arm maze (WRAM) and Morris maze (MM). Cognitive brain regions were assayed for changes in the GABAergic system by evaluating GAD protein, the synthesizing enzyme for GABA, and neurotrophins. On the WRAM, both progestin types impaired learning. Further, high-dose MPA impaired delayed memory retention on the WRAM, and exacerbated overnight forgetting on the MM. While neurotrophins were not affected by progesterone or MPA treatment, both progestin types altered GAD levels. MPA significantly and progesterone marginally decreased GAD levels in the hippocampus, and both MPA and progesterone significantly increased GAD levels in the entorhinal cortex. These findings suggest that MPA, the most commonly used progestin in HT, is detrimental to learning and two types of memory, and modulates the GABAergic system in cognitive brain regions, in aged surgically menopausal rats. These findings, combined with in vitro evidence that MPA is detrimental to neuronal health, indicates that MPA has negative effects for brain health and function.

Premarin improves memory, prevents scopolamine-induced amnesia and increases number of basal forebrain choline acetyltransferase positive cells in middle-aged surgically menopausal rats.

Conjugated equine estrogen (CEE) is the most commonly prescribed estrogen therapy, and is the estrogen used in the Women's Health Initiative study. While in-vitro studies suggest that CEE is neuroprotective, no study has evaluated CEE's effects on a cognitive battery and brain immunohistochemistry in an animal model. The current experiment tested whether CEE impacted: I) spatial learning, reference memory, working memory and long-term retention, as well as ability to handle mnemonic delay and interference challenges; and, II) the cholinergic system, via pharmacological challenge during memory testing and ChAT-immunoreactive cell counts in the basal forebrain. Middle-aged ovariectomized (Ovx) rats received chronic cyclic injections of either Oil (vehicle), CEE-Low (10 microg), CEE-Medium (20 microg) or CEE-High (30 microg) treatment. Relative to the Oil group, all three CEE groups showed less overnight forgetting on the spatial reference memory task, and the CEE-High group had enhanced platform localization during the probe trial. All CEE groups exhibited enhanced learning on the spatial working memory task, and CEE dose-dependently protected against scopolamine-induced amnesia with every rat receiving the highest CEE dose maintaining zero errors after scopolamine challenge. CEE also increased number of ChAT-immunoreactive neurons in the vertical diagonal band of the basal forebrain. Neither the ability to remember after a delay nor interference, nor long-term retention, was influenced by the CEE regimen used in this study. These findings are similar to those reported previously for 17 beta-estradiol, and suggest that CEE can provide cognitive benefits on spatial learning, reference and working memory, possibly through cholinergic mechanisms.