Neurobiological Mediators Research Articles

Influence of exercise on pain is associated with resting-state functional connections: A cross-sectional functional brain imaging study

Exercise is associated with lower prevalence and severity of pain, and is widely recommended for pain management. However, the mechanisms the exercise effect on pain remain unclear. In this study, we examined the association of exercise with pain and aimed to identify its neurobiological mediators. We utilized a baseline data of a clinical trial for people with low back pain. Participants reported pain intensity and exercise habit, as well as pain-related psychological and emotional assessments. We also obtained brain imaging data using a resting-state functional MRI and performed mediation analyses to identify brain regions mediating the exercise effect on pain. Forty-five people with low back pain (mean pain intensity = 59.6 and mean duration = 9.9 weeks) were included in this study. Participants with an exercise habit (n = 29) showed significant less pain compared to those without an exercise habit (n = 16). Mediation analysis using resting-state functional connectivity identified the left thalamus, right amygdala, and medial prefrontal cortex as statistical mediators of the exercise effect on pain (indirect effect = −0.460, 95% confidence interval = −0.767 to −0.153). In conclusion, our findings suggest that brain function of the specific regions is probably a neuro-mechanism of exercise alleviating pain.

An evaluation of bremelanotide injection for the treatment of hypoactive sexual desire disorder

ABSTRACT Introduction Female sexual response implies a deep intertwining between psychosocial and neurobiological mediators. Regulation of central melanocortin signaling may enhance sexual desire. In premenopausal women with hypoactive sexual desire disorder (HSDD), melanocortin receptor agonist bremelanotide (Vyleesi) has been hypothesized to trigger excitatory brain pathways. Areas covered Hereby we summarize bremelanotide’s proposed mechanism of action, pharmacokinetics, efficacy and safety data derived from clinical trials. A literature search of peer-reviewed publications on the current evidence on the pharmacotherapy with bremelanotide was performed using the PubMed database. Expert opinion Bremelanotide appears to be moderately safe and well-tolerated; the most common adverse reaction is nausea (40%). Although data from clinical trials demonstrated a significant change in validated questionnaires, the overall clinical benefit appears to be modest. However, these results should be interpreted in the light of the dramatic challenges in conducting well-designed clinical trials for female sexual dysfunction, due to the significant placebo effect of pharmacotherapy, and the frequent use of outcome measures that are likely to be highly susceptible to expectation biases, such as long periods of recall of sexual and emotional response.

Neuroscientist Details the Pandemic Stress We Have All Endured

Back to table of contents Previous article Next article APA & MeetingsFull AccessNeuroscientist Details the Pandemic Stress We Have All EnduredMark MoranMark MoranSearch for more papers by this authorPublished Online:13 Jul 2021https://doi.org/10.1176/appi.pn.2021.7.29Abstract“People hate ambiguity,” said Robert Sapolsky, Ph.D., yet it has been a defining feature of life in the face of global COVID-19 pandemic.Fear, uncertainty, ambiguity, unpredictability, lack of autonomous control, and deprivation of social contact—the past pandemic year has been a perfect stew activating the hormonal and neurobiological mediators of chronic stress, said Robert Sapolsky, Ph.D., in a closing address at APA’s online 2021 Annual Meeting.“We have been asked not to assemble, not to congregate, not to hang out and hook up, not to be social primates,” says Robert Sapolsky, Ph.D.“There is a beautiful and large literature by pioneers in [the field of psychological stress] going back decades showing precisely what the building blocks for psychological stress are,” Sapolsky said. “For the same external reality, you will feel more subjectively stressed, you are more likely to activate a stress response, and you are at more risk for stress-related disease if you feel like you have no outlet for the frustrations [you are experiencing]. Moreover, you will be more at risk if this circumstance is occurring [in a situation] where you feel like you have no control, no predictability, no information about how bad it will be. Additionally, psychological stress is built on a subjective perception that the external reality represents things getting worse. Finally, the absence of social support is perhaps the most central feature of all.”Sound familiar? It’s the nearly universal experience of the human race in the face of the global COVID-19 pandemic, Sapolsky said. He is the John A. and Cynthia Fry Gunn Professor of Neurology and Neurosurgery at Stanford University. His 2017 book, Behave: The Biology of Humans at Our Best and Our Worst, won the Phi Beta Kappa Award for Science and was listed among Best Books of the Year by The Washington Post, The New York Times, and The Wall Street Journal.He described laboratory experiments that have highlighted the distinction between risk—to which people have a wide variety of responses—and ambiguity, underscoring the special disdain humans have for uncertainty. “People across the board hate ambiguity,” Sapolsky said. “When you perform neuroimaging [of peoples’ brains] when they are dealing with ambiguity, ambiguity is preferentially lighting up the amygdala and insulate cortex, areas having to do with negative affect, fear, anxiety, disgust. We don’t like ambiguity.“What we have been facing this year is ambiguity, over and over,” he said. “How bad is this? How many are going to die? How long until there is a vaccine? Do you have immunity after the vaccine? Can you get infected again? We have spent the past year with the best of experts telling us, ‘It’s not clear.’”Most consequential of all has been the prohibition on social connectedness and Sapolsky showed images of COVID-19 youth parties (featuring Corona beer) and protests at state capitols against mask wearing and social distancing. These are evocative (horrendously, in this case, he said) of the human resistance to not being allowed to socialize. “We have been asked not to assemble, not to congregate, not to hang out and hook up, not to be social primates,” he said. “One of the most defining things about us being a primate is our profound sociality. This profoundly primatological trait of ours is what we have been asked to give up this year.”Sapolsky took his audience through a tour of 40 years of research exploring the relationship between chronic stress, depression, anxiety, and other mental illnesses. Most recently, this research has shown in laboratory studies that chronic stress can blunt emotional empathy.He closed his remarks with a reflection on this year’s Annual Meeting theme, “Finding Equity Through Advances in Mind and Brain in Unsettled Times.”“An entire literature has shown that unequal societies make for unhealthy ones, more violent ones and that unequal societies are ones that are less kind,” Sapolsky said. “We have seen the last year expanding our inequality in every possible way—who dies from this virus, who is shot unarmed by the police, who makes a fortune off of others during this pandemic. This has been a year of bringing out the worst of some of our behaviors.“I think the fact that it also brought out some of the most caring, some of the most extraordinarily self-sacrificial, altruistic behaviors is a mark of just how good we have been in the face of one of the worst types of stress you can imagine—and how tough it is going to be to lessen that inequity.” ■“Racial Inequality in Psychological Research: Trends of the Past and Recommendations for the Future” is posted here. ISSUES NewArchived

M140. WHAT HAPPENS IN THE BRAIN A FEW SECONDS BEFORE THE ONSET AND OFFSET OF AN HALLUCINATORY EPISODE?

BackgroundAuditory verbal hallucinations (AVH), the sense of “hearing voices” in the absence of a corresponding auditory source, are a major symptom in schizophrenia. Hemodynamic and electrophysiology studies have shown aberrant activation in fronto-temporal speech and language areas (Curcic-Blake et al., 2017 for review) – indicating neurobiological mediators relating to onset and duration of AVH episodes. However, unanswered is the question of specific neuronal precursors to the spontaneous cessation of an AVH episode. We therefore studied what happens in the brain a few seconds before both the onset and offset of an AVH episode.MethodsStructural and functional MRI data were collected from 44 patients diagnosed with a schizophrenia spectrum disorder, at three sites (University of Bergen, Norway, n=12; Medical University of Plovdiv, Bulgaria, n=13; Utrecht University Medical Center, Netherlands, n=19, total 25m, 19f, age 37.9+/-13.2 years). Symptom severity was assessed with the PANSS; mean total (+/-SD) 64.9+/-16.9; P3 hallucinatory behaviour 4.6+/-1.1. Additional assessments (not reported), scanner hardware and particulars of the MR acquisition varied between sites.Functional data were collected with a “symptom-capture” paradigm (Sommer et al., 2008), where subjects were instructed to press a button when a hallucinatory episode began, and another when the episode ended. Functional data were processed using an FSL FEAT pipeline, with additional filtering using the ICA_AROMA method. Data were then subjected to statistical analysis, contrasting hallucinatory with non-hallucinatory periods; higher-level analysis allowed comparison with findings from previous meta-analyses (Kompus et al. 2011, Jardri et al., 2011).A number of regions of interest were selected based on an initial PCA, in addition to regions nominated in the meta-analyses. For each region, for each start- and end-of-hallucination event, a time-course was extracted for the interval t=-10 to +15sec with respect to button-press onset. Time-courses were aligned and group-averaged (rejecting outliers iteratively) to yield a model time-course for start- and end- hallucinatory events in each region. Permutation analysis (n=5000) was performed to identify differential effects between start and end events.ResultsFunctional block-analysis revealed several clusters of activation, including among others the left fronto-temporal language areas (superior temporal gyrus and Broca’s area). Similar patterns were present on a per-site basis.Time-course analysis demonstrated a differential effect in the left paracingulate sulcus, characterized by a significant dip in activation (Δ=-158iu, p=0.021) at the end-of-hallucination events, in contrast to a significant peak (Δ=35iu, p=0.0142) at the start-of-hallucination events. This activity preceded the motor response for the same events.DiscussionClusters identified in the block-analysis at group-level were consistent with findings from meta-analyses; this attests to the validity of the source data and initial processing. The novel finding of anticipatory neuronal activity in the paracingulate region, differentiated between onset and offset of AVH- events, complements recent findings of reduced functional connectivity (Alonso-Solís et al., 2015) and morphological differences (Garrison et al., 2019) in the same region. This suggests that the paracingulate region may be crucial in both the initiation and the cessation of an AVH-episode and speaks to a kind of regulatory role for the region. This may in turn point to differential action of excitatory and inhibitory transmitters at a lower level of explanation.

(300) Neuropeptide Y and ALLO: Potential Neurobiological Mediators of Exercise Benefits for Pain Sensitivity in Chronic Pain and PTSD: Preliminary CDA2 Findings

This study assessed the effects of acute exercise challenge testing (MAX-EX), as well as progressive exercise training, on Neuropeptide Y (NPY) and ALLO, two anti-stress and anti-nociceptive neurohormones, according to their relationship with pain sensitivity in a male and female population of civilians and Veterans with comorbid chronic pain and PTSD. The pilot sample (N=5) was 40% male (n=2), 60% female (n=3) with mean age of 35 years. Before exercise training, there were only small, non-significant positive correlations between MAX-EX test-induced increases in NPY or ALLO and indices of pain sensitivity (pain threshold and tolerance) assessed via a cold pressor test performed 30’ after the MAX-EX test (Δ NPY with pain threshold: =.36, p=.43; ΔALLO with pain tolerance: =-.37, p=.47). After exercise training, correlations between MAX-EX test-induced increases in NPY or ALLO and indices of pain sensitivity were high (ΔNPY with pain threshold: =.96, p

Intra-cortical myelin mediates personality differences.

ObjectiveDifferences in myelination in the cortical mantle are important neurobiological mediators of variability in cognitive, emotional, and behavioral functioning. Past studies have found that personality traits reflecting such variability are linked to neuroanatomical and functional changes in prefrontal and temporo‐parietal cortices. Whether these effects are partially mediated by the differences in intra‐cortical myelin remains to be established.MethodTo test this hypothesis, we employed vertex‐wise intra‐cortical myelin maps in n = 1,003 people from the Human Connectome Project. Multivariate regression analyses were used to test for the relationship between intra‐cortical myelin and each of the five‐factor model’s personality traits, while accounting for age, sex, intelligence quotient, total intracranial volume, and the remaining personality traits.ResultsNeuroticism negatively related to frontal‐pole myelin and positively to occipital cortex myelin. Extraversion positively related to superior parietal myelin. Openness negatively related to anterior cingulate myelin, while Agreeableness positively related to orbitofrontal myelin. Conscientiousness positively related to frontal‐pole myelin and negatively to myelin content in the dorsal anterior cingulate cortex.ConclusionsIntra‐cortical myelin levels in brain regions with prolonged myelination are positively associated with personality traits linked to favorable outcome measures. These findings improve our understanding of the neurobiological underpinnings of variability in common behavioral dispositions.

Increases in orbitofrontal cortex thickness following antidepressant treatment are associated with changes in resting state autonomic function in adolescents with major depression – Preliminary findings from a pilot study

In adults with major depressive disorder (MDD), effective treatment has been associated with increases in both heart rate variability (HRV) and cortical thickness. However, the impact of treatment on these indices has not yet been examined in adolescents. Cortical thickness and HRV were measured in twelve adolescents with MDD before and after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI). We examined treatment-related changes in depression symptoms, HRV, heart rate (HR), and cortical thickness, and analyzed correlations among these change indices. At follow-up, patients showed significantly decreased depression severity, increased HRV and increased thickness of the left medial orbitofrontal cortex (OFC). Clinical improvement was associated with increased HRV and decreased HR. Increased HRV was associated with increased cortical thickness of left lateral OFC and superior frontal cortex. Due to the small sample size, results represent preliminary findings that need replication. Further, in the absence of a placebo arm, we cannot confirm that the observed effects are due solely to medication. These preliminary findings suggest that SSRI treatment in adolescents impacts both cortical thickness and autonomic functioning. Confirmation of these findings would support OFC thickness and HRV as neurobiological mediators of treatment outcome.

Perceived discrimination and cardiovascular health disparities: a multisystem review and health neuroscience perspective.

There are distinct racial disparities in cardiovascular disease (CVD) risk, with Black individuals at much greater risk than White individuals. Although many factors contribute to these disparities, recent attention has focused on the role of discrimination as a stress-related factor that contributes to racial disparities in CVD. As such, it is important to understand the mechanisms by which discrimination might affect CVD. Recent studies have examined these mechanisms by focusing on neurobiological mediators of CVD risk. Given this increase in studies, a systematic review of perceived discrimination and neurobiological mediators of CVD risk is warranted. Our review uses a multisystem approach to review studies on the relationship between perceived discrimination and (1) cardiovascular responses to stress, (2) hypothalamic-pituitary-adrenocortical axis function, and (3) the immune system, as well as (4) the brain systems thought to regulate these parameters of peripheral physiology. In addition to summarizing existing evidence, our review integrates these findings into a conceptual model describing multidirectional pathways linking perceived discrimination with a CVD risk.

6.2 Harsh Physical Punishment and Aggression: Neurobiological Mediators and Influences of Other Forms of Environmental Risk

Consistent links exist between harsh physical punishment during childhood and risk for later aggressive and violent behavior in adolescence. Recent work has focused on how changes in brain regions such as the amygdala may mediate the linkage between harsh physical punishment and later aggression and violence. Past research has found that forms of early life stress, such as child maltreatment, are related to higher amygdala activity to facial displays of threat, but few links have been reported between amygdala activity and problem behavior in these sample groups.

Neurobiological Mediators of Squalor-dwelling Behavior

Squalor-dwelling behavior has been characterized as living in conditions so unsanitary that feelings of revulsion are elicited among visitors. This behavior is commonly associated with an insensitivity to distress/disgust and a failure to understand the direness of one’s living situation, which leads to social isolation and impairment in quality of life. Etiologically, several associations have been described in the literature, including age-related decline, lower socioeconomic status, and rural dwelling status. Primary neuropsychiatric disorders, such as psychosis, alcoholism, dementia, personality disorders, developmental delays, and learning or physical disabilities are frequently seen in squalor-dwelling individuals. However, none of these disorders seems to be necessary or sufficient to explain the behavior. Neurobiologically, squalor-dwelling behavior has been associated with frontal lobe dysfunction as evidenced by executive dysfunction; however, cognitive impairments also fail to completely explain this behavior. The purpose of this report is to describe a typical case of squalor-dwelling behavior and use it as an example to illustrate the complexity of uncovering the neurobiological basis for this maladaptive personal and public health threat. Neuroimaging findings from our case and a review of the literature point toward decreased activity in the insular cortex and the amygdala as a unifying biological explanation for squalor-dwelling behaviors.

The shared neuroanatomy and neurobiology of comorbid chronic pain and PTSD: therapeutic implications.

Chronic pain and posttraumatic stress disorder (PTSD) are disabling conditions that affect biological, psychological, and social domains of functioning. Clinical research demonstrates that patients who are affected by chronic pain and PTSD in combination experience greater pain, affective distress, and disability than patients with either condition alone. Additional research is needed to delineate the interrelated pathophysiology of chronic pain and PTSD, with the goal of facilitating more effective therapies to treat both conditions more effectively; current treatment strategies for chronic pain associated with PTSD have limited efficacy and place a heavy burden on patients, who must visit various specialists to manage these conditions separately. This article focuses on neurobiological factors that may contribute to the coprevalence and synergistic interactions of chronic pain and PTSD. First, we outline how circuits that mediate emotional distress and physiological threat, including pain, converge. Secondly, we discuss specific neurobiological mediators and modulators of these circuits that may contribute to chronic pain and PTSD symptoms. For example, neuropeptide Y, and the neuroactive steroids allopregnanolone and pregnanolone (together termed ALLO) have antistress and antinociceptive properties. Reduced levels of neuropeptide Y and ALLO have been implicated in the pathophysiology of both chronic pain and PTSD. The potential contribution of opioid and cannabinoid system factors also will be discussed. Finally, we address potential novel methods to restore the normal function of these systems. Such novel perspectives regarding disease and disease management are vital to the pursuit of relief for the many individuals who struggle with these disabling conditions.

Effects of exercise on the desire to smoke and physiological responses to temporary smoking abstinence: a crossover trial.

Exercise has been shown to attenuate cigarette cravings during temporary smoking abstinence; however, the mechanisms of action are not clearly understood. The objectives of the study were to compare the effects of three exercise intensities on desire to smoke and explore potential neurobiological mediators of desire to smoke. Following overnight abstinence, 40 participants (25 males, 18-59 years) completed three 15 min sessions of light-, moderate-, or vigorous-intensity exercise on a cycle ergometer in a randomized crossover design. Ratings of desire to smoke were self-reported pre- and post-exercise and heart rate variability was measured throughout. Saliva and blood were analyzed for cortisol and noradrenaline in a sub-sample. Exercise influenced desire to smoke (F [2, 91] = 7.94, p < 0.01), with reductions greatest immediately after vigorous exercise. There were also significant time x exercise intensity interaction effects for heart rate variability and plasma noradrenaline (F [8, 72] = 2.23, p = 0.03), with a bias in noradrenaline occurring between light and vigorous conditions (adjusted mean difference [SE] = 2850 ng/ml [592], p < 0.01) at 5 min post-exercise. There was no interaction of time x exercise intensity for plasma and salivary cortisol levels. These findings support the use of vigorous exercise to reduce cigarette cravings, showing potential alterations in a noradrenergic marker.

Mesocorticolimbic monoamine correlates of methamphetamine sensitization and motivation.

Methamphetamine (MA) is a highly addictive psychomotor stimulant, with life-time prevalence rates of abuse ranging from 5–10% world-wide. Yet, a paucity of research exists regarding MA addiction vulnerability/resiliency and neurobiological mediators of the transition to addiction that might occur upon repeated low-dose MA exposure, more characteristic of early drug use. As stimulant-elicited neuroplasticity within dopamine neurons innervating the nucleus accumbens (NAC) and prefrontal cortex (PFC) is theorized as central for addiction-related behavioral anomalies, we used a multi-disciplinary research approach in mice to examine the interactions between sub-toxic MA dosing, motivation for MA and mesocorticolimbic monoamines. Biochemical studies of C57BL/6J (B6) mice revealed short- (1 day), as well as longer-term (21 days), changes in extracellular dopamine, DAT and/or D2 receptors during withdrawal from 10, once daily, 2 mg/kg MA injections. Follow-up biochemical studies conducted in mice selectively bred for high vs. low MA drinking (respectively, MAHDR vs. MALDR mice), provided novel support for anomalies in mesocorticolimbic dopamine as a correlate of genetic vulnerability to high MA intake. Finally, neuropharmacological targeting of NAC dopamine in MA-treated B6 mice demonstrated a bi-directional regulation of MA-induced place-conditioning. These results extend extant literature for MA neurotoxicity by demonstrating that even subchronic exposure to relatively low MA doses are sufficient to elicit relatively long-lasting changes in mesocorticolimbic dopamine and that drug-induced or idiopathic anomalies in mesocorticolimbic dopamine may underpin vulnerability/resiliency to MA addiction.

Serum NGF, BDNF and IL-6 levels in postpartum mothers as predictors of infant development: the influence of affective disorders.

BackgroundEarly adverse experiences are associated with increased risk of developing psychiatric disorders, although little is known about the neurobiological mediators involved. The mechanisms by which early environmental influences may mediate vulnerability in the development of offspring await further investigation. The present study correlated the NGF, BDNF, IL-6 and cortisol levels of mothers with postpartum affective disorders (PPAD) with infant development.MethodsA longitudinal study was performed with 152 pregnant women and their infants. Between 60 and 120 days after delivery, women were interviewed and provided biological samples for biochemical analysis, and the infants were examined for neurobiological-motor development.ResultsOverall, the mothers' history of affective disorders, PPAD and anxiety disorder were associated with infant motor development. Using an adjusted linear regression analysis, PPAD (p = 0.049), maternal anxiety disorder (p = 0.043), NGF level (p = 0.034) and infant cortisol level (p = 0.013) were associated with infant motor development. Using a factorial analysis of primary components, two components were retained. The psychological factor was characterized by a positive loading of a history of affective disorder, PPAD and anxiety disorder. For the biological factor, infant cortisol adhered negatively with infant motor development, but NGF was positively associated. The psychological factor had a negative association, but the biological factor had a positive association with infant motor development.ConclusionsThere are few studies that have focused on the relationship of biomarkers and infant neurodevelopment. Our study points that psychological and biological factors are associated with infant motor development, however the causal relationship between these factors is still to be defined.

Placebo and Nocebo in Interventional Pain Management: A Friend or a Foe – Or Simply Foes?

The present evidence illustrates that the placebo effect depends on a variety of neurochemical and neurophysiological mechanisms, which are measurable and modifiable. However, the placebo response is inexorably tied to the treatment context. All medical treatments take place in a particular context; this context includes the therapist’s attitudes, psychosocial factors affecting the therapeutic relationship, and the patient’s mindset. Therapeutic efficacy at least in part is attributable to the concordance between the proposed treatment and the patient’s belief system. It is this fraction of the therapeutic response that is commonly called the placebo effect. More formally, the placebo effect is defined as that part of the therapeutic response that is not attributable to the properties of active ingredients. A proposed model of the placebo effect includes a complex reaction with induction, psychophysiological mediators, neurobiological mediators, and actualization of effects. Similarly, nocebo hyperalgesia is also explained by neurobiological mechanisms resulting in anxiety and nocebo hyperalgesia. Functional neuroanatomy of placebo indicates an anticipation phase and modulation phase or placebo response. In modern medicine it is well recognized that the treatment effect of many active interventions is related to both an active treatment component and the placebo component. Thus, clinical implications are enormous as such placebo analgesia and nocebo hyperalgesia are not simply response biases. Instead, they are the product of neurophysiological processes that modulate the integration of the nociceptive signals throughout the central nervous system. Thus, it has been suggested that clinicians should not try to avoid the placebo effect. On the contrary, they should try to potentiate it, since this is a very important clinical implication. From the research perspective, the emerging knowledge of placebo continues to cast doubts on the appropriateness of the double-blind placebo-control design in assessing efficacy of treatment - specifically involving interventional techniques or surgery. The research setting itself may introduce nocebo hyperalgesia. Key words: Placebo, placebo analgesia, placebo treatment, placebo effect, nocebo, nocebo hyperalgesia, psychophysiological mediators, neurobiological mediators, inert agent

Vulnerability of reactive skin to electric current perception – a pilot study implicating mast cells and the lymphatic microvasculature

Sensitive/reactive skin is regarded as a manifestation of sensory irritation. This susceptibility condition to various exogenous factors suggests the intervention of some neuropeptides and other neurobiological mediators. Mast cells are among the putative implicated cells. The present immunohistochemical and morphometric study was performed on two groups of 36 gender- and age-matched subjects complaining or not from reactive skin as determined by electric current perception. In the mid upper part of the dermis, the numerical density in mast cells and the size of the microvasculature were assessed distinguishing the blood and lymphatic vessels. Globally, the distributions of data were large in reactive skin. This condition was characterized by a prominent increase in both the numerical density in mast cells and the overall size of the lymphatics. By contrast, no difference was found in the size of cutaneous blood vessels. More precisely, it appeared that a subgroup of people with reactive skin exhibited these changes contrasting with some other individuals whose data remained close to the normal range. Mast cells and lymphatics are probably involved in the process of sensory irritation affecting a subgroup of the population.

Exercise and Bipolar Disorder: A Review of Neurobiological Mediators

Extant evidence indicates that individuals with bipolar disorder (BD) are differentially affected by overweight/obesity and abdominal obesity. Excess weight is associated with a more complex illness presentation, non-recovery, and recurrence. Herein, we sought to review literature describing the effects of structured individualized physical exercise on disparate neurobiological substrates implicated in the pathophysiology of BD. We conducted a PubMed search of all English-language articles published between 1966 and July 2008 with BD cross-referenced with the following search terms: exercise, neurobiology, pathophysiology, pathoetiology, brain, cognition, neuroplasticity, and neurodegeneration. Articles selected for review were based on adequacy of sample size, the use of standardized experimental procedures, validated assessment measures, and overall manuscript quality. Contemporary models of disease pathophysiology in BD implicate disturbances in cellular resilience, plasticity, and survival in the central nervous system. Individualized exercise interventions are capable of alleviating the severity of affective and cognitive difficulties in heterogeneous samples. It is posited that exercise is a pleiotropic intervention that engages aberrant neurobiological systems implicated in metabolism, immuno-inflammatory function, and cellular respiration. Structured exercise regimens exert a salutary effect on interacting networks mediating metabolism, immuno-inflammatory function, and cellular respiration. In keeping this view, buttressed by controlled evidence describing robust anti-depressant effects with exercise (e.g., public health dose), a testable hypothesis is that structured exercise is capable of improving psychiatric and somatic health in BD.

Sex differences in negative affective response during nicotine withdrawal

This study examined physiological indicants of the neurobiological mediators of negative affect during acute nicotine withdrawal. Eighty subjects (41 male) were assigned to one of four groups (24-h deprived or nondeprived dependent smokers, occasional smokers, and nonsmokers) and participated in an instructed fear conditioning paradigm involving cued administration of electric shock. Negative affective response was measured with fear-potentiated startle during cues that signaled electric shock and during the postcue offset recovery period. Salivary cortisol and self-report measures were also collected. Fear-potentiated startle results indicated that affective recovery postcue offset was delayed in nicotine-deprived women. Nicotine-deprived women also displayed elevated cortisol levels throughout the fear conditioning procedure.

Smoking as a complex but critical covariate in neurobiological studies of posttraumatic stress disorders: a review

As smoking rates in the general population continue to fall in response to new information and changing social values, the continued high rate of smoking among persons with psychiatric disorders has caught the attention of society at many levels: public health officials, medical and mental health care providers, and concerned family members alike. As a consequence, research studies aimed at quantifying the problem and understanding its cause have increased dramatically over the past several years. The following review first examines epidemiological studies that have revealed a bidirectional causal relationship between tobacco dependence and posttraumatic stress disorder (PTSD), one of several mental health disorders in which tobacco dependence remains prevalent and resistant to intervention. Second, we use a translational neuroscience perspective to discuss possible neurobiological mediators of the relationship between PTSD and tobacco dependence, hoping to spur further human and animal research that will elucidate pathogenetic mechanisms involved and inspire novel treatment interventions. Finally, to enable more effective clinical research in this area, we provide an overview of effective scientific methods for assessing and managing 'smoking status' as an experimental variable in clinical research studies of PTSD as well as other mental health disorders.

Characterization of Cell Death Pathways in Human Immunodeficiency Virus-Associated Encephalitis

Human immunodeficiency virus (HIV)-associated dementia is a neurodegenerative syndrome characterized by cognitive decline, personality change, and motor deficits. HIV-associated encephalitis (HAE), the neuropathology responsible for HIV-associated dementia, involves the formation of multinucleated giant cells or syncytia. In this article we describe the apoptotic pathways activated in the brains of HAE-affected patients. Approximately 50% of multinuclear giant cells exhibited apoptotic DNA fragmentation as detected by the terminal dUTP nick-end labeling technique. In addition, the presence of syncytia in the frontal cortex of approximately 35% of HAE patients correlated with the number of cells expressing the HIV-1 protein p24. Histochemical and immunohistochemical analyses revealed that HAE-associated syncytia underwent apoptosis through a mitochondrial pathway previously delineated for HIV-1 envelope-elicited syncytia in vitro. We observed over-expression of the mammalian target of rapamycin (mTOR), a kinase that mediates activation of the pro-apoptotic transcription factor p53, and p53-dependent up-regulation of two effectors of mitochondrial apoptosis, namely the BH3-only proteins Puma and transglutaminase type 2 (TG2). Interestingly, although mTOR activation and Puma induction were observed in dying syncytia and neurons, IkB phosphorylation and TG2 up-regulation were only found in syncytia. These findings provide substantial new information on the cell death mechanisms that regulate HAE, suggesting an important pathogenetic role of syncytia in the disease.