Chronic Low Dose Neutron Exposure Results in Altered Neurotransmission Properties of the Hippocampus-Prefrontal Cortex Axis in Both Mice and Rats.

The proposed deep space exploration to the moon and later to Mars will result in astronauts receiving significant chronic exposures to space radiation (SR). SR exposure results in multiple neurocognitive impairments. Recently, our cross-species (mouse/rat) studies reported impaired associative memory formation in both species following a chronic 6-month low dose exposure to a mixed field of neutrons (1 mGy/day for a total dose pf 18 cGy). In the present study, we report neutron exposure induced synaptic plasticity in the medial prefrontal cortex, accompanied by microglial activation and significant synaptic loss in the hippocampus. In a parallel study, neutron exposure was also found to alter fluorescence assisted single synaptosome LTP (FASS-LTP) in the hippocampus of rats, that may be related to a reduced ability to insert AMPAR into the post-synaptic membrane, which may arise from increased phosphorylation of the serine 845 residue of the GluA1 subunit. Thus, we demonstrate for the first time, that low dose chronic neutron irradiation impacts homeostatic synaptic plasticity in the hippocampal-cortical circuit in two rodent species, and that the ability to successfully encode associative recognition memory is a dynamic, multicircuit process, possibly involving compensatory changes in AMPAR density on the synaptic surface.

Theta-modulated oscillatory transcranial direct current stimulation over posterior parietal cortex improves associative memory.

Associative memory (AM) reflects the ability to remember and retrieve multiple pieces of information bound together thus enabling complex episodic experiences. Despite growing interest in the use of transcranial direct current stimulation (tDCS) for the modulation of AM, there are inconsistent evidence regarding its benefits. An alternative to standard constant tDCS could be the application of frequency-modulated tDCS protocols, that mimic natural function-relevant brain rhythms. Here, we show the effects of anodal tDCS oscillating in theta rhythm (5 Hz; 1.5 ± 0.1 mA) versus constant anodal tDCS and sham over left posterior parietal cortex on cued recall of face-word associations. In a crossover design, each participant completed AM assessment immediately following 20-min theta-oscillatory, constant, and sham tDCS, as well as 1 and 5 days after. Theta oscillatory tDCS increased initial AM performance in comparison to sham, and so did constant tDCS. On the group level, no differences between oscillatory and constant tDCS were observed, but individual-level analysis revealed that some participants responded to theta-oscillatory but not to constant tDCS, and vice versa, which could be attributed to their different physiological modes of action. This study shows the potential of oscillatory tDCS protocols for memory enhancement to produce strong and reliable memory-modulating effects which deserve to be investigated further.

High-frequency neuromodulation improves obsessive-compulsive behavior.

Nearly one billion people worldwide suffer from obsessive-compulsive behaviors1,2, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning3,4, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing5,6. We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.

Whole-brain irradiation differentially modifies neurotransmitters levels and receptors in the hypothalamus and the prefrontal cortex.

BACKGROUND: Whole-brain radiotherapy is a primary treatment for brain tumors and brain metastasis, but it also induces long-term undesired effects. Since cognitive impairment can occur, research on the etiology of secondary effects has focused on the hippocampus. Often overlooked, the hypothalamus controls critical homeostatic functions, some of which are also susceptible after whole-brain radiotherapy. Therefore, using whole-brain irradiation (WBI) in a rat model, we measured neurotransmitters and receptors in the hypothalamus. The prefrontal cortex and brainstem were also analyzed since they are highly connected to the hypothalamus and its regulatory processes. METHODS: Male Wistar rats were exposed to WBI with 11 Gy (Biologically Effective Dose = 72 Gy). After 1 month, we evaluated changes in gamma-aminobutyric acid (GABA), glycine, taurine, aspartate, glutamate, and glutamine in the hypothalamus, prefrontal cortex, and brainstem according to an HPLC method. Ratios of Glutamate/GABA and Glutamine/Glutamate were calculated. Through Western Blott analysis, we measured the expression of GABAa and GABAb receptors, and NR1 and NR2A subunits of NMDA receptors. Changes were analyzed comparing results with sham controls using the non-parametric Mann-Whitney U test (p < 0.05). RESULTS: WBI with 11 Gy induced significantly lower levels of GABA, glycine, taurine, aspartate, and GABAa receptor in the hypothalamus. Also, in the hypothalamus, a higher Glutamate/GABA ratio was found after irradiation. In the prefrontal cortex, WBI induced significant increases of glutamine and glutamate, Glutamine/Glutamate ratio, and increased expression of both GABAa receptor and NMDA receptor NR1 subunit. The brainstem showed no statistically significant changes after irradiation. CONCLUSION: Our findings confirm that WBI can affect rat brain regions differently and opens new avenues for study. After 1 month, WBI decreases inhibitory neurotransmitters and receptors in the hypothalamus and, conversely, increases excitatory neurotransmitters and receptors in the prefrontal cortex. Increments in Glutamate/GABA in the hypothalamus and Glutamine/Glutamate in the frontal cortex indicate a neurochemical imbalance. Found changes could be related to several reported radiotherapy secondary effects, suggesting new prospects for therapeutic targets.

Monochromatic Blue Light Activates Suprachiasmatic Nucleus Neuronal Activity and Promotes Arousal in Mice Under Sevoflurane Anesthesia.

Background: Monochromatic blue light (MBL), with a wavelength between 400-490 nm, can regulate non-image-forming (NIF) functions of light in the central nervous system. The suprachiasmatic nucleus (SCN) in the brain is involved in the arousal-promoting response to blue light in mice. Animal and human studies showed that the responsiveness of the brain to visual stimuli is partly preserved under general anesthesia. Therefore, this study aimed to investigate whether MBL promotes arousal from sevoflurane anesthesia via activation of the SCN in mice. Methods: The induction and emergence time of sevoflurane anesthesia under MBL (460 nm and 800 lux) exposure was measured. Cortical electroencephalograms (EEGs) were recorded and the burst-suppression ratio (BSR) was calculated under MBL during sevoflurane anesthesia. The EEGs and local field potential (LFP) recordings with or without locally electrolytic ablated bilateral SCN were used to further explore the role of SCN in the arousal-promoting effect of MBL under sevoflurane anesthesia. Immunofluorescent staining of c-Fos was conducted to reveal the possible downstream mechanism of SCN activation. Results: Unlike the lack of effect on the induction time, MBL shortened the emergence time and the EEG recordings showed cortical arousal during the recovery period. MBL resulted in a significant decrease in BSR and a marked increase in EEG power at all frequency bands except for the spindle band during 2.5% sevoflurane anesthesia. MBL exposure under sevoflurane anesthesia enhances the neuronal activity of the SCN. These responses to MBL were abolished in SCN lesioned (SCNx) mice. MBL evoked a high level of c-Fos expression in the prefrontal cortex (PFC) and lateral hypothalamus (LH) compared to polychromatic white light (PWL) under sevoflurane anesthesia, while it exerted no effect on c-Fos expression in the ventrolateral preoptic area (VLPO) and locus coeruleus (LC) c-Fos expression. Conclusions: MBL promotes behavioral and electroencephalographic arousal from sevoflurane anesthesia via the activation of the SCN and its associated downstream wake-related nuclei. The clinical implications of this study warrant further study.

Orbitofrontal control of visual cortex gain promotes visual associative learning.

The orbitofrontal cortex (OFC) encodes expected outcomes and plays a critical role in flexible, outcome-guided behavior. The OFC projects to primary visual cortex (V1), yet the function of this top-down projection is unclear. We find that optogenetic activation of OFC projection to V1 reduces the amplitude of V1 visual responses via the recruitment of local somatostatin-expressing (SST) interneurons. Using mice performing a Go/No-Go visual task, we show that the OFC projection to V1 mediates the outcome-expectancy modulation of V1 responses to the reward-irrelevant No-Go stimulus. Furthermore, V1-projecting OFC neurons reduce firing during expectation of reward. In addition, chronic optogenetic inactivation of OFC projection to V1 impairs, whereas chronic activation of SST interneurons in V1 improves the learning of Go/No-Go visual task, without affecting the immediate performance. Thus, OFC top-down projection to V1 is crucial to drive visual associative learning by modulating the response gain of V1 neurons to non-relevant stimulus.

The effect of HF-rTMS over the left DLPFC on stress regulation as measured by cortisol and heart rate variability.

The prefrontal cortex, and especially the Dorsolateral Prefrontal Cortex (DLPFC), plays an inhibitory role in the regulation of the Hypothalamic-Pituitary-Adrenal (HPA) axis under stressful situations. Moreover, recent evidence suggests that a sustained DLPFC activation is associated with adaptive stress regulation in anticipation of a stressful event, leading to a reduced stress-induced amygdala response, and facilitating the confrontation with the stressor. However, studies using experimental manipulation of the activity of the DLPFC before a stressor are scarce, and more research is needed to understand the specific role of this brain area in the stress-induced physiological response. This pre-registered study investigated the effect on stress regulation of a single excitatory high frequency (versus sham) repetitive transcranial magnetic stimulation (HF-rTMS) session over the left DLPFC applied before the Trier Social Stress Test in 75 healthy young women (M = 21.05, SD = 2.60). Heart rate variability (HRV) and salivary cortisol were assessed throughout the experimental protocol. The active HF-rTMS and the sham group showed a similar cognitive appraisal of the stress task. No differences in HRV were observed during both the anticipation and the actual confrontation with the stress task and therefore, our results did not reflect DLPFC-related adaptive anticipatory adjustments. Importantly, participants in the active HF-rTMS group showed a lower cortisol response to stress. The effect of left prefrontal HF-rTMS on the stress system provides further critical experimental evidence for the inhibitory role played by the DLPFC in the regulation of the HPA axis.

Investigating the impact of mobile range electromagnetic radiation on the medial prefrontal cortex of the rat during working memory.

Research has been focused on the effects of radiofrequency electromagnetic radiation (RF-EMR) emitted from a mobile phone on general health, especially the nervous system. The purpose of this study was to investigate the impact of RF-EMR on the brain mechanism of rats by recording local field potentials (LFPs) signals during working memory (WM) task. Subjects were exposed to 900 MHz from a dipole antenna daily for three hours. Exposure was applied, first on a short term base (1 week) and then on a long term base (4 weeks). Behavioral parameters were measured weekly while rats performed T-maze tasks in two types of normal and delayed. LFPs signals were simultaneously recorded by implanted microelectrode arrays on the medial prefrontal cortex (mPFC) of rats. Results showed a significant increase (*p < 0.05) in the task completion time of exposed rats which vanished shortly after the end of short term RF-EMR exposure. Before exposure, during correctly performed delayed tasks, an increase (peak) in power changes of theta band (4-12 Hz) was observed. But during correctly performed normal tasks, an increase appeared only by applying RF-EMR exposure. The similarity in power changes pattern of theta band in both types of tasks was observed after long term exposure. Classification accuracy of LFPs in truly done normal and delayed tasks was compared in pre and post-exposure states. Initial classification accuracy was 84.2 % which decreased significantly (*P < 0.05) after exposure. These observations indicated that RF-EMR may cause unusual brain functioning which is temporary at least for short term exposure.

Altered Cognitive Flexibility and Synaptic Plasticity in the Rat Prefrontal Cortex after Exposure to Low (≤15 cGy) Doses of 28Si Radiation.

This study has established the impact that 1-15 cGy 600 MeV/n 28Si radiation had on cognitive flexibility performance, glutamatergic synaptic transmission and plasticity in the prelimbic area (PrL) of the medial prefrontal cortex (mPFC) of ∼10-month-old (at the time of irradiation) male Wistar rats. Exposure to 1 cGy 600 MeV/n 28Si ions resulted in significantly impaired performance in the simple (SD) and compound discrimination (CD) stages of the attentional set shifting (ATSET) task. However, there was a pronounced non-linear dose response for cognitive impairment. Should similar effects occur in astronauts, the impairment of SD performance would result in a decreased ability to identify and learn the "rules" required to respond to new tasks/situations, while the impaired CD performance would result in a decreased ability to identify and maintain focus on relevant aspects of the task being conducted. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem solving. Exposure to 1, 5 and 10 cGy resulted in a significant reduction in UCFlex performance, in an apparent all-or-none responsive manner. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. After completion of the cognitive flexibility testing, in vitro electrophysiological assessments of glutamatergic synaptic transmission and plasticity were performed in slices of the PrL cortex of 10 cGy irradiated rats. Extracellular recordings of field excitatory postsynaptic potentials revealed that radiation significantly decreased long-term depression in layer L5. Patch-clamp whole cell recordings in pyramidal neurons of the L2-3 revealed reduced frequency of spontaneous excitatory postsynaptic currents indicating alterations in presynaptic glutamate release and impaired neuronal spiking (e.g., decreased action potential amplitudes) in irradiated neurons. However, there was no obvious correlation between magnitudes of these electrophysiological decrements and the cognitive performance status of the irradiated rats. These data suggest that while radiation-induced changes in synaptic plasticity in the PrL cortex may be associated with cognitive impairment, they are most likely not the sole determinant of the incidence and severity of such impairments.

Effect of Gum Chewing on PFC Activity During Discomfort Sound Stimulation.

The prefrontal cortex (PFC) is sensitive to the stress exposure and involved in stress coping. And the effects of gum chewing on the stress have been studied using NIRS. However, when measuring NIRS on PFC during gum chewing, blood flows in shallow tissues (scalp, skin, muscle) might be affected. A NIRS used in the present study first, which has a short distance (1 cm) and the usual (3 cm) source-detector (S-D) regression, can allow eliminating shallow tissues effect of gum chewing. The aim of this study was to investigate the hypothesis that gum chewing activates the right prefrontal cortex (PFC) in stress coping against negative sounds (NS) from the International Affective Digitized Sounds-2 (IADS) as a mental stress task. NS showed activation in the right PFC. There was a significant difference between NS, and NS with Gum, where NS with Gum showed an increased PFC activity, increased alpha wave appearance rate, a higher value in heart rate level, and a higher VAS score indicating 'pleasant'. Gum chewing activated right PFC activity while exposed to negative sounds from IADS as a mental stress task.

Effects of prefrontal transcranial direct current stimulation on autonomic and neuroendocrine responses to psychosocial stress in healthy humans.

Prolonged or repeated activation of the stress response can have negative psychological and physical consequences. The prefrontal cortex (PFC) is thought to exert an inhibitory influence on the activity of autonomic and neuroendocrine stress response systems. In this study, we further investigated this hypothesis by increasing PFC excitability using transcranial direct current stimulation (tDCS). Healthy male participants were randomized to receive either anodal (excitatory) tDCS (n = 15) or sham stimulation (n = 15) over the left dorsolateral prefrontal cortex (DLPFC) immediately before and during the exposure to a psychosocial stress test. Autonomic (heart rate (HR) and its variability) and neuroendocrine (salivary cortisol) parameters were assessed. One single session of excitatory tDCS over the left DLPFC (i) reduced HR and favored a larger vagal prevalence prior to stress exposure, (ii) moderated stress-induced HR acceleration and sympathetic activation/vagal withdrawal, but (iii) had no effect on stress-induced cortisol release. However, anodal tDCS over the left DLPFC prevented stress-induced changes in the cortisol awakening response. Finally, participants receiving excitatory tDCS reported a reduction in their levels of state anxiety upon completion of the psychosocial stress test. In conclusion, this study provides first insights into the efficacy of one single session of excitatory tDCS over the left DLPFC in attenuating autonomic and neuroendocrine effects of psychosocial stress exposure. These findings might be indicative of the important role of the left DLPFC, which is a cortical target for noninvasive brain stimulation treatment of depression, for successful coping with stressful stimuli.

Corticostriatal stimulation compensates for medial frontal inactivation during interval timing.

Prefrontal dysfunction is a common feature of brain diseases such as schizophrenia and contributes to deficits in executive functions, including working memory, attention, flexibility, inhibitory control, and timing of behaviors. Currently, few interventions improve prefrontal function. Here, we tested whether stimulating the axons of prefrontal neurons in the striatum could compensate for deficits in temporal processing related to prefrontal dysfunction. We used an interval-timing task that requires working memory for temporal rules and attention to the passage of time. Our previous work showed that inactivation of the medial frontal cortex (MFC) impairs interval timing and attenuates ramping activity, a key form of temporal processing in the dorsomedial striatum (DMS). We found that 20-Hz optogenetic stimulation of MFC axon terminals increased curvature of time-response histograms and improved interval-timing behavior. Furthermore, optogenetic stimulation of terminals modulated time-related ramping of medium spiny neurons in the striatum. These data suggest that corticostriatal stimulation can compensate for deficits caused by MFC inactivation and they imply that frontostriatal projections are sufficient for controlling responses in time.

Single session high definition transcranial direct current stimulation to the cerebellum does not impact higher cognitive function.

The prefrontal cortex is central to higher order cognitive function. However, the cerebellum, generally thought to be involved in motor control and learning, has also been implicated in higher order cognition. Recent work using transcranial direct current stimulation (tDCS) provides some support for right cerebellar involvement in higher order cognition, though the results are mixed, and often contradictory. Here, we used cathodal high definition tDCS (HD-tDCS) over the right cerebellum to assess the impact of HD-tDCS on modulating cognitive performance. We predicted that stimulation would result in performance decreases, which would suggest that optimal cerebellar function is necessary for cognitive performance, much like the prefrontal cortex. That is, it is not simply a structure that lends support to complete difficult tasks. While the expected cognitive behavioral effects were present, we did not find effects of stimulation. This has broad implications for cerebellar tDCS research, particularly for those who are interested in using HD-tDCS as a way of examining cerebellar function. Further implications, limitations, and future directions are discussed with particular emphasis on why null findings might be critical in developing a clear picture of the effects of tDCS on the cerebellum.

Repetitive transcranial magnetic stimulation in chronic tension-type headache: A pilot study.

Background & objectives: Tension-type headache (TTH) is the most common type of primary headache disorder. Its chronic form is often the most ignored and challenging to treat. Transcranial magnetic stimulation (TMS) is a novel technique in the treatment of chronic pain. The aim of this pilot study was to explore the effect of low-frequency repetitive TMS (rTMS) on pain status in chronic TTH (CTTH) by subjective and objective pain assessment. Methods: Patients (n=30) diagnosed with CTTH were randomized into rTMS (n=15) and placebo (n=15) groups in this study. Pre-intervention detailed history of patients was taken. Numerical Rating Scale (NRS) for Pain and questionnaires [Headache Impact Test-6 (HIT-6), McGill Pain Questionnaire, Pain Beliefs Questionnaire, Coping Strategies Questionnaire, State-Trait Anxiety Inventory Test, Hamilton Rating Scale for Depression and WHO-Quality of Life Questionnaire-Brief version] were filled, and objective assessments such as nociceptive flexion reflex (NFR) and conditioned pain modulation were done. The tests were repeated after 20 sessions (5 days/week). In the rTMS group, 1200 pulses in eight trains of 150 pulses each were given at 1Hz over the right dorsolateral prefrontal cortex (RDLPFC). In the placebo group, the rTMS coil was placed such that magnetic stimulation did not reach the cortex. Results: The NRS score decreased significantly (P<0.001) and NFR thresholds increased significantly (P=0.011) in the rTMS group when compared to placebo group. Interpretation & conclusions: Subjective improvements in the NRS, HIT-6, McGill Present Pain Intensity, trait of anxiety and psychological pain beliefs were observed. The increase in the thresholds of NFR served as an objective marker for improvement in pain status. Further studies need to be done to confirm our preliminary findings.

Feasibility and clinical effects of theta burst stimulation in youth with major depressive disorders: An open-label trial.

BACKGROUND: Conventional treatments for youth depression, such as antidepressants, have modest efficacy, side effects, and ongoing controversies regarding safety. Repetitive transcranial magnetic stimulation (rTMS), specifically theta burst stimulation (TBS), applied to the dorsolateral prefrontal cortex (DLPFC) has demonstrated efficacy for the treatment of depression in adults. However, the feasibility and clinical response to TBS for youth depression has yet to be explored. METHODS: Twenty participants between the ages of 16 to 24 years old with MDD were recruited. The intervention consisted of 10 treatment sessions over the course of two weeks, in which participants received intermittent TBS and continuous TBS stimulation to the left and right DLPFC, respectively. Change in the Hamilton Rating Scale for Depression (HRSD-17) score was the primary outcome. Clinical assessments occurred at baseline, after the fifth treatment session, and within a week after treatment completion. RESULTS: Of the twenty participants, eighteen received all TBS sessions, and seventeen completed all clinical assessments. There was a significant reduction in depressive symptoms following treatment completion (p < 0.001). Four of the twenty patients had more than 50% reduction in their depressive symptoms, two of whom achieved remission. All participants received and tolerated at least six daily TBS treatments with no major adverse events. LIMITATIONS: Study was an uncontrolled, open-label design. CONCLUSION: Ten sessions of TBS was feasible, well tolerated, and appeared to have clinical effects for the treatment of depressed youth. Future sham-controlled randomized trials are warranted to validate these findings in a larger cohort of youth depression.

Does rTMS on brain areas of mirror neurons lead to higher improvements on symptom severity and empathy compared to the rTMS standard procedure? - Results from a double-blind interventional study in individuals with major depressive disorders.

BACKGROUND: A key feature of major depressive disorders is the lack of emotional processing such as empathy. To counter this, we tested, if brain stimulation on areas rich of mirror neurons on the left inferior parietal lobe (lIPL) might improve emotional processing, including empathy, compared to a standard brain stimulation on the left dorsolateral prefrontal cortex (lDLPFC). METHODS: Twenty inpatients (mean age: 38.9 years; 55% females) with severe major depressive disorders and stable treatment of sertraline at therapeutic dosages were randomly assigned to either the rTMS condition on areas of mirror neuron stimulation, that is, the left inferior parietal lobe (rTMS-lIPL), or to the left dorsolateral prefrontal cortex (rTMS-lDLPFC; control condition). Interventions lasted for two consecutive weeks (2 × 5 interventions of 30'). At baseline and at the end of the study, patients completed questionnaires on current mood state and emotion regulation. In parallel, experts rated patients' depression severity. RESULTS: Mood improved over time, but more so in the control condition, compared to the rTMS-lIPL condition (medium-large effect sizes). Emotion regulation improved over time; specifically, empathy improved, but only in the rTMS-lIPL condition, compared to the control condition. Symptoms of depression decreased over time, but more so in the rTMS- lIPL condition. CONCLUSIONS: The pattern of results suggests that among inpatients with severe major depressive disorders, and compared to a standard procedure of rTMS, rTMS targeting on areas rich of mirror neurons appeared to improve emotion regulation, and specifically empathy, while there was no advantage on acute mood.

Inverse effects of tDCS over the left versus right DLPC on emotional processing: A pupillometry study.

BACKGROUND AND OBJECTIVES: The Dorsolateral prefrontal cortex (DLPFC) is implicated in cognitive and emotional responses. Yet, research that investigates the causal role of the left versus right DLPFC during the processes of emotion appraisal is lacking. In the current study, transcranial direct current stimulation (tDCS) was used to disentangle the functional lateralization of the DLPFC on emotional processing in response to the anticipation of, and subsequent confrontation with emotional stimuli in healthy volunteers. METHODS: Forty-eight subjects received both active and sham (on separate days) anodal tDCS over either the left (N = 24) or right (N = 24) DLPFC. Subjects' pupil dilation (PD, a physiological marker of cognitive resource allocation) was recorded while performing an appraisal task in which negative and positive emotion eliciting images were presented, each preceded by an informative cue indicating the valence of the upcoming stimulus. RESULTS: As compared to sham stimulation, left DLPFC anodal tDCS resulted in increased PD when confronted with negative emotional images, whereas right DLPFC anodal tDCS resulted in decreased PD when confronted with emotional images, irrespective of valence. LIMITATIONS: The interpretation of pupil dilation in response to emotional stimuli is limited. CONCLUSION: These findings suggest inverse lateralized DLPFC effects on cognitive resource allocation (as measured by pupillary responses) when confronted with emotional stimuli. The current findings may shed some light on mechanisms that explain the antidepressant effects of non-invasive brain stimulation of the left DLPFC.

A novel neuromodulation strategy to enhance the prefrontal control to treat pain.

Effective pharmacological treatment options for chronic pain remain very limited, and continued reliance on opioid analgesics has contributed to an epidemic in the United States. On the other hand, nonpharmacologic neuromodulatory interventions provide a promising avenue for relief of chronic pain without the complications of dependence and addiction. An especially attractive neuromodulation strategy is to optimize endogenous pain regulatory circuits. The prefrontal cortex is known to provide top-down control of pain, and hence neuromodulation methods that selectively enhance the activities in this brain region during pain episodes have the potential to provide analgesia. In this study, we designed a low-frequency (2 Hz) electrical stimulation protocol to provide temporally and spatially specific enhancement of the prefrontal control of pain in rats. We showed that low-frequency electrical stimulation of the prelimbic region of the prefrontal cortex relieved both sensory and affective responses to acute pain in naive rats. Furthermore, we found that low-frequency electrical stimulation of the prefrontal cortex also attenuated mechanical allodynia in a rat model of chronic pain. Together, our findings demonstrated that low-frequency electrical stimulation of the prefrontal cortex represents a promising new method of neuromodulation to inhibit pain.

Improving working memory and pain inhibition in older persons using transcranial direct current stimulation.

The aim of the present study was to examine whether transcranial Direct Current Stimulation (tDCS) could enhance working memory and pain inhibition in older persons. Fifteen volunteers (7 women, 8 men; mean ± SD: 64 ± 4.4 y.o.) participated in two tDCS sessions during which an n-back task was performed with two levels of working memory load, while painful stimulation was delivered at the ankle. The experiment included five within-subject counterbalanced conditions (pain alone and 0-back or 2-back with or without pain) performed twice during each session. Compared with the pre-tDCS baseline, anodal tDCS decreased response times and improved pain inhibition by working memory in the 2-back condition (p < 0.01), but not in the 0-back or pain alone conditions, while sham tDCS produced no effect (all p > 0.3). These results indicate that working memory and pain inhibition can be improved by tDCS in older persons.

Continuous theta-burst stimulation over the dorsolateral prefrontal cortex inhibits improvement on a working memory task.

Theta-burst stimulation (TBS) over the dorsolateral prefrontal cortex (DLPFC) may be more effective for modulating cortical excitability compared to standard repetitive transcranial magnetic stimulation. However, the impact of intermittent (iTBS) and continuous TBS (cTBS) on working memory (WM) is poorly studied. The aim of our study was to compare the effects of iTBS and cTBS on WM over the left and right DLPFC. iTBS, cTBS or sham stimulation was administered over the right and left hemisphere of fifty-one healthy human subjects. WM was assessed before and after TBS using the 1-back, 2-back, and 3-back tasks. We found classical practice effects in the iTBS and the sham group: WM performance improved following stimulation as measured by the discriminability index. However, this effect could not be observed in the cTBS group. We did not find any hemisphere-dependent effects, suggesting that the practice effect is not lateralized, and TBS affects WM performance in a comparable manner if administered either over the left or the right hemisphere. We propose that our findings represent a useful addition to the literature of TBS-induced effects on WM. Moreover, these results indicate the possibility of clarifying processes underlying WM performance changes by using non-invasive brain stimulation.