A shea butter-based ketamine ointment: The antidepressant effects of transdermal ketamine in rats.

The delayed onset of monoaminergic antidepressants and disadvantages of traditional administration routes created the need for alternative non-invasive delivery methods with rapid onset therapeutic effect. Ketamine attracted attention as a fast-acting glutamatergic antidepressant with ideal physiochemical properties for alternative routes of administration. However, there is no sufficient data for its transdermal use in depression. In this proof-of-concept study, we investigated the antidepressant effects of transdermal ketamine delivered via a novel ointment with skin protective, emulsifying and permeation enhancing properties. A shea butter-based 5% (w/w) ketamine ointment or a drug-free vehicle ointment were applied to the shaved dorsal skin of male Wistar rats for 2 days, twice a day. Behavioral despair, locomotor activity and anxiety-like behavior were respectively assessed in the forced swim test (FST), open field test (OFT), and elevated plus maze (EPM). The pharmacokinetic profile of the ointment was analyzed with high-performance liquid chromatography. Transdermal ketamine ameliorated behavioral despair without altering general locomotor activity and anxiety-like behavior, showing that skin-friendly drug carriers like shea butter may constitute promising alternatives to current routes of delivery for ketamine. Tested transdermal method aims to provide more sustainable drug delivery for long-term treatment schedules. Future studies can investigate its long-term use, side effects and abuse liability.

Functional near-infrared spectroscopy shows that object relative clauses are more difficult to process than subject relative clauses in Turkish.

It was suggested that processing subject relative clauses (SRCs) is universally easier than processing object relative clauses (ORCs) based on the studies carried out in head-initial languages such as English and German. However, studies in head-final languages such as Chinese and Basque contradicted this claim. Turkish is also a head-final language. Existing relative clause processing literature in Turkish is based solely on behavioural metrics. Even though an ORC processing disadvantage was suggested for Turkish, the results were not conclusive. Therefore, we aimed to investigate the neural dynamics of relative clause processing in Turkish. We asked 14 native Turkish speakers to answer yes/no questions about 24 sentences each containing either a SRC or ORC while their prefrontal hemodynamic activity was recorded with functional near-infrared spectroscopy. Our findings revealed hemodynamic activity in the lateral portions of the left prefrontal cortex for both conditions. However, hemodynamic activity was more widespread in prefrontal regions in ORC compared to SRC condition. Even though the behavioural metrics failed to produce a significant difference between the conditions, direct ORC > SRC contrast revealed significant activity in the left inferior frontal cortex, a region heavily involved in language processing, as well as in left and right dorsolateral prefrontal cortices, which are also known to be involved in language processing-related and conflict monitoring-related processes, respectively. Our findings indicate that processing ORCs is more difficult and requires further prefrontal resources than processing SRCs in Turkish, thus refuting the head-directionality-based explanations of relative clause processing asymmetries.

Sensory stimulation via the visual, auditory, olfactory and gustatory systems can modulate mood and depression.

Depression is one of the most common mental disorders, predicted to be the leading cause of disease burden by the next decade. There is great deal of emphasis on the central origin and potential therapeutics of depression whereby the symptomatology of depression has been interpreted and treated as brain generated dysfunctions filtering down to the periphery. This top-down approach has found strong support from clinical work and basic neuroscientific research. Nevertheless, despite great advances in our knowledge of the aetiology and therapeutics of depression, success in treatment is still by no means assured. As a consequence, a wide net has been cast by both clinicians and researchers in search of more efficient therapies for mood disorders. As a complementary view, the present integrative review advocates approaching mood and depression from the opposite perspective: a bottom-up view that starts from the periphery. Specifically, evidence is provided to show that sensory stimulation via the visual, auditory, olfactory, and gustatory systems can modulate depression. The review shows how-depending on several parameters-unisensory stimulation via these modalities can ameliorate or aggravate depressive symptoms. Moreover, the review emphasises the bidirectional relationship between sensory stimulation and depression. Just as peripheral stimulation can modulate depression, depression in turn affects-and in most cases impairs-sensory reception. Furthermore, the review suggests that combined use of multisensory stimulation may have synergistic ameliorative effects on depressive symptoms over and above what has so far been documented for unisensory stimulation.

Paw preference is associated with behavioural despair and spatial reference memory in male rats.

Paw preference, one of the well-studied behavioural markers of asymmetry, has been associated with affective states and pathologies such as behavioural despair, a rodent model of clinical depression. However, a consistent differential effect of paw preference has not been observed for cognitive functions. In order to investigate the affective properties of paw preference together with its potential cognitive effects, we grouped male Wistar rats as left- or right-pawed, and tested them in the forced swim test and Morris water maze for behavioural despair and spatial memory performance, respectively. We found that left-pawed rats were significantly more susceptible to behavioural despair, while spatial learning performance of the two groups were not different over a five-day Morris water maze task. Left-pawed rats, however, displayed a better reference memory than the right-pawed ones on the subsequent probe trial when the hidden platform of the maze was removed. These findings indicate paw preference as a vulnerability factor for behavioural despair and reveal a previously unknown association between left-paw preference and reference memory performance as assessed in the probe trial of the Morris water maze.

Functional Near-Infrared Spectroscopy Indicates That Asymmetric Right Hemispheric Activation in Mental Rotation of a Jigsaw Puzzle Decreases With Task Difficulty.

Mental rotation (MR) is a cognitive skill whose neural dynamics are still a matter of debate as previous neuroimaging studies have produced controversial results. In order to investigate the underlying neurophysiology of MR, hemodynamic responses from the prefrontal cortex of 14 healthy subjects were recorded with functional near-infrared spectroscopy (fNIRS) during a novel MR task that had three categorical difficulty levels. Hemodynamic activity strength (HAS) parameter, which reflects the ratio of brain activation during the task to the baseline activation level, was used to assess the prefrontal cortex activation localization and strength. Behavioral data indicated that the MR requiring conditions are more difficult than the condition that did not require MR. The right dorsolateral prefrontal cortex (DLPFC) was found to be active in all conditions and to be the dominant region in the easiest task while more complex tasks showed widespread bilateral prefrontal activation. A significant increase in left DLPFC activation was observed with increasing task difficulty. Significantly higher right DLPFC activation was observed when the incongruent trials were contrasted against the congruent trials, which implied the possibility of a robust error or conflict-monitoring process during the incongruent trials. Our results showed that the right DLPFC is a core region for the processing of MR tasks regardless of the task complexity and that the left DLPFC is involved to a greater extent with increasing task complexity, which is consistent with the previous neuroimaging literature.

Low cognitive competence as a vulnerability factor for behavioral despair in rats.

Elucidating the multi-faceted relationship between cognitive competence and affective states is a major pursuit in behavioral sciences. Mood disorders constitute a good research model for this question, as cognitive impairment may accompany clinical depression and persist after full remission. This suggests cognitive dysfunction as an etiological factor of depression, rather than an epiphenomenon. Complementing clinical studies, animal models utilizing well-controlled, systematic paradigms are essential to elucidate the complex relationship between cognitive competence and affective states. In current set of experiments, we investigated the extent to which cognitive competence determines the stress response in Wistar rats by utilizing two well-established spatial memory paradigms with different degrees of complexity together with the forced swim test. We revealed that rats with low cognitive competence as assessed by learning performance in the Y-Maze, but not in the radial arm maze, were significantly more vulnerable to behavioral despair. In contrast, rats with high cognitive competence were resilient to the negative effects of the forced swim test, irrespective of the spatial memory task used. These results point to a nonlinear relationship between spatial memory performance and behavioral despair, suggesting that different types of cognitive functioning may have differential effects on affective processes.

Psychomotor retardation in depression: A critical measure of the forced swim test.

DSM-5 lists 9 different symptoms for major depressive disorder and dictates that either "depressed mood" or "loss of interest or pleasure" should be present for diagnosis. Both are relatively high-level symptoms of the complex affecto-cognitive disease. However, the single most common behavioral paradigm and the gold standard animal (rodent) test for depression, the forced swim test (FST), measures a low-level mechanical feature that resembles "psychomotor retardation" observed in depression. This symptom refers to the slowing down of cognitive processes and an associated reduction in mobility. Likewise, the FST involves placing a rodent (mouse or rat) in a water-filled cylinder to measure its escape-related mobility over periods of immobility. Avoiding the term depression, this particular form of immobility observed in the FST was termed behavioral despair. Behavioral despair does not correlate with general mobility levels of the animal as measured in an open field test; and FST can reliably differentiate antidepressant treatments from other treatments that merely lead to increased mobility. It is therefore not a mere reflection of decreased physical energy or locomotion, but indicates the level of psychomotor activity of the animal. This review discusses the clinical significance and neurobiology of psychomotor retardation, and evaluates how FST, measuring this mechanical aspect of the disease, emerges as a reliable method and a critical step in antidepressant research.

Oral ketamine alleviates behavioral despair without cognitive impairment in Wistar rats.

Ketamine is a non-competitive NMDA receptor antagonist used as a major anesthetic agent, especially in children. It has also been shown that at sub-anesthetic concentrations, ketamine has acute antidepressant properties. The rapid-onset nature of this effect makes it a promising alternative for classical antidepressants targeting the monoaminergic system. However, ketamine can lead to various cognitive side effects depending on the user/subject as well as its concentration and administration method, and it is still questionable whether this drug can be utilized as a reliable antidepressant. Here, we test the effects of continuous low dose oral ketamine on behavioral despair and spatial working memory in male Wistar rats. We found that 0.4 mg/day, but not 0.2 mg/day, ketamine in 30 ml juice has an antidepressant effect emerging in just 10 consecutive days as measured by means of forced swim tests without impairing spatial working memory performance in the Y-maze for as long as 30 days. These results suggest that, once clinically optimized, long-term use of low dose oral ketamine can produce antidepressant effects.

Head-turning asymmetry: A novel lateralization in rats predicts susceptibility to behavioral despair.

Behavioral markers of laterality reflecting underlying neurobiological asymmetries between the cerebral hemispheres are related to differential susceptibility to mood disorders. In the present study, we investigated the strength and consistency of a novel behavioral lateralization, head-turning asymmetry, and its relation to behavioral despair in adult female Wistar rats. Head-turning biases were determined in a test where water-deprived rats had to turn their head to right or left to gain access to a water dispenser. This procedure was administered 4 times over 8days. Four days after the head-turning test, rats were subjected to two forced swim tests separated by 24h to examine the relationship between head-turning asymmetry and behavioral despair. Rats were administered one more head-turning test session after the second swim test to determine whether behavioral despair induction altered head-turning direction preferences. Results revealed significant correlations among head-turning test sessions indicating head-turning direction preference as measured with our method is a consistent behavioral lateralization. Although most rats were strongly lateralized, there was no bias in either direction at the population level. Importantly, we found that while rats with a left head-turning bias showed a significant increase in the duration of immobility from the first to the second swim test, right-biased rats performed similarly in the two swim tests. Behavioral despair induction did not change head-turning direction preferences. The present findings show that head-turning asymmetries are predictive of mood disorders in rats and may serve as the basis to elucidate the mechanisms relating hemispheric asymmetries to depression in humans.

Automated Neuroanatomical Relation Extraction: A Linguistically Motivated Approach with a PVT Connectivity Graph Case Study.

Identifying the relations among different regions of the brain is vital for a better understanding of how the brain functions. While a large number of studies have investigated the neuroanatomical and neurochemical connections among brain structures, their specific findings are found in publications scattered over a large number of years and different types of publications. Text mining techniques have provided the means to extract specific types of information from a large number of publications with the aim of presenting a larger, if not necessarily an exhaustive picture. By using natural language processing techniques, the present paper aims to identify connectivity relations among brain regions in general and relations relevant to the paraventricular nucleus of the thalamus (PVT) in particular. We introduce a linguistically motivated approach based on patterns defined over the constituency and dependency parse trees of sentences. Besides the presence of a relation between a pair of brain regions, the proposed method also identifies the directionality of the relation, which enables the creation and analysis of a directional brain region connectivity graph. The approach is evaluated over the manually annotated data sets of the WhiteText Project. In addition, as a case study, the method is applied to extract and analyze the connectivity graph of PVT, which is an important brain region that is considered to influence many functions ranging from arousal, motivation, and drug-seeking behavior to attention. The results of the PVT connectivity graph show that PVT may be a new target of research in mood assessment.

Toward Building Hybrid Biological/in silico Neural Networks for Motor Neuroprosthetic Control.

In this article, we introduce the Bioinspired Neuroprosthetic Design Environment (BNDE) as a practical platform for the development of novel brain-machine interface (BMI) controllers, which are based on spiking model neurons. We built the BNDE around a hard real-time system so that it is capable of creating simulated synapses from extracellularly recorded neurons to model neurons. In order to evaluate the practicality of the BNDE for neuroprosthetic control experiments, a novel, adaptive BMI controller was developed and tested using real-time closed-loop simulations. The present controller consists of two in silico medium spiny neurons, which receive simulated synaptic inputs from recorded motor cortical neurons. In the closed-loop simulations, the recordings from the cortical neurons were imitated using an external, hardware-based neural signal synthesizer. By implementing a reward-modulated spike timing-dependent plasticity rule, the controller achieved perfect target reach accuracy for a two-target reaching task in one-dimensional space. The BNDE combines the flexibility of software-based spiking neural network (SNN) simulations with powerful online data visualization tools and is a low-cost, PC-based, and all-in-one solution for developing neurally inspired BMI controllers. We believe that the BNDE is the first implementation, which is capable of creating hybrid biological/in silico neural networks for motor neuroprosthetic control and utilizes multiple CPU cores for computationally intensive real-time SNN simulations.

Right-but not left-paw use in female rats provides advantage in forced swim tests.

Left- and right-pawed adult female Wistar rats were subjected to forced swimming on two consecutive days. Compared to the right-pawed group, left- pawed rats displayed significantly increased immobility from the first to the second swim test and remained significantly more immobile in the second swim test. Both groups performed similarly in spatial learning in the Morris water maze suggesting that left- pawed rats are differentially and specifically susceptible to depressogenic treatment.

Sensorimotor modulation of mood and depression: in search of an optimal mode of stimulation.

Depression involves a dysfunction in an affective fronto-limbic circuitry including the prefrontal cortices, several limbic structures including the cingulate cortex, the amygdala, and the hippocampus as well as the basal ganglia. A major emphasis of research on the etiology and treatment of mood disorders has been to assess the impact of centrally generated (top-down) processes impacting the affective fronto-limbic circuitry. The present review shows that peripheral (bottom-up) unipolar stimulation via the visual and the auditory modalities as well as by physical exercise modulates mood and depressive symptoms in humans and animals and activates the same central affective neurocircuitry involved in depression. It is proposed that the amygdala serves as a gateway by articulating the mood regulatory sensorimotor stimulation with the central affective circuitry by emotionally labeling and mediating the storage of such emotional events in long-term memory. Since both amelioration and aggravation of mood is shown to be possible by unipolar stimulation, the review suggests that a psychophysical assessment of mood modulation by multimodal stimulation may uncover mood ameliorative synergisms and serve as adjunctive treatment for depression. Thus, the integrative review not only emphasizes the relevance of investigating the optimal levels of mood regulatory sensorimotor stimulation, but also provides a conceptual springboard for related future research.

Duration discrimination by musicians and nonmusicians.

This study investigated the effects of stimulus modality, standard duration, sex, and laterality in duration discrimination by musicians and nonmusicians. Seventeen musicians (M age = 24.1 yr.) and 22 nonmusicians (M age = 26.8 yr.) participated. Auditory (1,000 Hz) and tactile (250 Hz) sinusoidal suprathreshold stimuli with varying durations were used. The standard durations tested were 0.5 and 3.0 sec. Participants discriminated comparison stimuli which had durations slightly longer and shorter than the standard durations. Difference limens were found by the method of limits and converted to Weber fractions based on the standard durations. Musicians had lower, i.e., better, Weber fractions than nonmusicians in the auditory modality, but there was no significant difference between musicians and nonmusicians in the tactile modality. Auditory discrimination was better than tactile discrimination. Discrimination improved when the standard duration was increased both for musicians and nonmusicians. These results support previous findings of superior auditory processing by musicians. Significant differences between discrimination in the millisecond and second ranges may be due to a deviation from Weber's law and the discontinuity of timing in different duration ranges reported in the literature.

A comparative study of health related quality of life, psychological well-being, impact of illness and stigma in epilepsy and migraine.

This study aimed to show the difference of epilepsy from another chronic neurological disorder with episodic manifestations (CDEM): migraine. Seventy persons with epilepsy (PWE), 56 persons with migraine (PWM) and 45 healthy control participants (HCs) were included. The groups were compared in terms of demographics, quality of life, depression and self-esteem. The PWE and PWM were also compared with regard to stigma, impact of the illness, disclosure, application of spiritual/traditional healing methods, limitations, most affected life areas, and restrictions. Results showed that the PWM had lower quality of life values than the PWE and the HCs, while there was no difference among the groups in depression and self-esteem. Results also show higher unemployment levels and lower marriage rates for the PWE, where education levels were equal. Although the PWM had higher impact of illness values, the PWE were shown to have higher stigma, more concealment behavior, and higher traditional/spiritual healing application ratios. Also, the PWM emphasized the importance of being "able to fulfil daily living, social and work activities", while the PWE emphasized the need for "independence" constantly. These results indicate that, although both migraine and epilepsy are CDEMs, they have different levels of impact on patients' lives. The impacts are socially greater in epilepsy and extend beyond the neurological condition itself.

The effects of systemic and intratumoral interleukin-12 treatment in C6 rat glioma model.

OBJECTIVE: Cytokine based immunotherapy has long been an exciting field for many investigators aiming to provide an effective alternative treatment modality for glioma management. Among these cytokines, interleukin-12 (IL-72) plays a crucial role in mediating inflammatory and antitumoral activity on the host defence. We have investigated the therapeutic role of systemic and local delivery of IL-12 in C6 rat glioma model and compared these two modalities. METHODS: The donor C6 glioma cells were injected stereotactically to 32 Wistar rats and right frontal tumor formation was established in all subjects. The rats were evenly divided into four groups as intratumoral (i.t.) control group (Group IA), intraperitoneal (i.p.) control group (Group IB), i.t. treatment group (Group II) and i.p. treatment group (Group III). Magnetic resonance imaging were performed to 72 rats (three from each group) on the seventh post-inoculation day. Recombinant mouse IL-12 (rmIL-12) was administered via i.t. (0.1 microg 5 microl/day/rat) and i.p. (0.1 microg 20 microl/day/rat) routes to treatment groups between days 9 and 11 following tumor inoculation, for 3 consecutive days. The rats which were unresponsive to the external stimuli, unable to feed themselves or having severe neurological impairment were decapitated and the specimens were histopathologically examined. RESULTS: The subjects of Group ILL (i.p.) showed a statistically significant prolongation in survival time (mean = 39 days) when compared to the control group (mean = 31.7 days) (p = 0.035) and Group II (i.t.) (mean = 24.5 days) (p = 0.005). Histopathologic examination of Group III revealed markedly increased intratumoral and peritumoral lymphocyte infiltration compared with the other groups. CONCLUSION: This study demonstrated that systemic administration of IL- 12 in C6 glioma model in rats prolongs the survival, probably by stimulating the cellular immunity leading to lymphocytic infiltration.

Effects of BNST lesions in female rats on forced swimming and navigational learning.

The bed nucleus of the stria terminalis (BNST) in the forebrain shows sexual dimorphism in its neuroanatomical connectivity and neurochemical characteristics. The structure is involved in many behavioral and motivational phenomena particularly related to coping with stress. Female rats differ from males in responding to stressful situations such as forced swimming and navigational learning in the water maze. It was previously shown that bilateral damage to the BNST in male Wistar rats aggravated depression as measured by forced swim tests, but did not impair navigational learning in the water maze. The present study extended the findings to female rats demonstrating that bilateral electrolytic lesions of the BNST increased immobility and decreased climbing compared to sham-operated controls, but failed to affect performance in the water maze. Additionally, lesions did not alter behavior in the open field and the elevated plus-maze tests suggesting not only that the modulation of depression by BNST lesions is specific, but also providing support for the view that the BNST may not necessarily be critically involved in anxiety.

BNST lesions aggravate behavioral despair but do not impair navigational learning in rats.

The bed nucleus of the stria terminalis (BNST) is a basal forebrain structure involved in many motivational processes closely linked to stress regulation. The present study investigated the effect of bilateral lesions of the BNST in male Wistar rats on behavioral despair and navigational learning in the Morris water maze both of which present stressful challenges. Compared to controls, BNST-lesioned animals displayed longer duration of immobility in the second of two forced swim tests used to assess behavioral despair but performed similarly in the water maze task. The present results indicate strongly that the BNST is involved in the modulation of behavioral despair. Experimentally induced depression by BNST lesions does not impair learning and memory in the water maze suggesting a possible dissociation between BNST-mediated depression and cognitive performance.

A single day of constant light (L/L) provides immunity to behavioral despair in female rats maintained on an L/D cycle.

The present experiment investigated the potentially ameliorative effect of exposure to light in the dark phase of an 12:12 h daily lighting schedule (12L/12D cycle) on behavioral despair, an animal model of depression based on two forced swim tests separated by 24 h. Experimental groups of female Wistar rats were maintained on the 12L/12D cycle except for a single exposure to 12 h of light treatment in the dark phase of the 12L/12D cycle. Control animals were treated similarly except for light treatment. Animals then underwent one of two sets of behavioral tests starting on either the day light (or control) treatment ended (No Delay groups) or 24 h thereafter (Delay groups). The treatment for subgroups of light-treated and control animals tested with or without delay consisted of either two forced swim tests separated by 24 h or testing in the open field and elevated plus maze. Results indicated that a single exposure to a 12-h light treatment has protective effect on behavioral despair in groups tested with or without delay as measured by shorter duration of immobility in the second swim test compared to the controls. Light-treated and control animals behaved similarly in the open field and elevated plus-maze tests.

Changes in quality of life and self-perspective related to surgery in patients with temporal lobe epilepsy.

PURPOSE: To evaluate changes in intractable epilepsy patients in terms of quality of life, depression, anxiety, stigma, and impact of epilepsy before and after surgery. METHODS: Twenty patients with intractable temporal lobe epilepsy who were waiting for surgery (pre-SAH group) and 21 patients who had already undergone surgery (post-SAH group) were studied. All patients received SF-36, Beck Depression Inventory, State-Trait Anxiety Inventory, stigma and impact of epilepsy inventories, and a form asking their own perspectives about epilepsy and surgery. RESULTS: Post-SAH group scored higher on all subscales of SF-36, with only RE scores being significantly better (t=-1.98, P=.05). Although depression, anxiety, and stigma scores were higher in pre-SAH group, only impact of epilepsy scores were significantly higher in pre-SAH group (t=-2.951, P=.005). Seizure frequency and comorbidity had significant effects on QOL where amount of AEDs and QOL were negatively related (r=-0.318, P<0.05). Both groups stated lack of independence and social activities as the main concern (48.8%) and recovery from epilepsy as the most important expectation from surgery (85.4%). Post-surgical group mentioned the difference in their life after surgery as independence and increase in social activities (47.6%). CONCLUSION: QOL of patients after surgery was found to be better than before surgery. Results also revealed that seizure frequency, comorbidity, and anti-epileptic medication affected health related QOL negatively. Impact of epilepsy levels was found to be higher among the pre-SAH patients. Finally, independence seemed to be the most important concern and gain for Turkish epilepsy patients.