Electrical stimulation of the trigeminal nerve improves olfaction in healthy individuals: A randomized, double-blind, sham-controlled trial.

BACKGROUND: Both activated by environmental odorants, there is a clear role for the intranasal trigeminal and olfactory nerves in smell function. Unfortunately, our ability to perceive odorants decreases with age or with injury, and limited interventions are available to treat smell loss. OBJECTIVE: We investigated whether electrical stimulation of the trigeminal nerve via trigeminal nerve stimulation (TNS) or transcranial direct current stimulation (tDCS) modulates odor sensitivity in healthy individuals. METHODS: We recruited 20 healthy adults (12 Female, mean age = 27) to participate in this three-visit, randomized, double-blind, sham-controlled trial. Participants were randomized to receive one of three stimulation modalities (TNS, tDCS, or sham) during each of their visits. Odor detection thresholds were obtained at baseline, immediately post-intervention, and 30-min post-intervention. Furthermore, participants were asked to complete a sustained attention task and mood assessments before odor detection testing. RESULTS: Findings reveal a timeXcondition interaction for guaiacol (GUA) odorant detection thresholds (F (3.188, 60.57) = 3.833, P = 0.0125), but not phenyl ethyl alcohol (PEA) odorant thresholds. At 30-min post-stimulation, both active TNS and active tDCS showed significantly increased sensitivity to GUA compared to sham TNS (Sham TNS = -8.30% vs. Active TNS = 9.11%, mean difference 17.43%, 95% CI 5.674 to 29.18, p = 0.0044; Sham TNS = -8.30% vs. Active tDCS = 13.58%, mean difference 21.89%, 95% CI 10.47 to 33.32, p = 0.0004). CONCLUSION: TNS is a safe, simple, noninvasive method for boosting olfaction. Future studies should investigate the use of TNS on smell function across different stimulation parameters, odorants, and patient populations.

Anxiety-related shifts in smell function in children and adolescents.

Anxious adults show changes in smell function that are consistent with a durable shift in sensitivity toward particular odorants and away from others. Little is known regarding the development of these changes, including whether they exist in youth, are stable during the transition from childhood to adolescence, and whether odorant properties (e.g. trigeminal features, hedonic valence) affect anxiety-related differences in detection. To address this, we measured smell detection thresholds to phenyl ethyl alanine (PEA), a rose-like odorant with little trigeminal properties, and guaiacol (GUA), a smoke-like odorant with high trigeminal properties. These thresholds were measured at baseline and after an acute stress challenge, the Trier Social Stress Tests, in 131 healthy youth (in 4th, 7th, and 10th grades, age 9-16 years) that reported normal to elevated levels of anxiety. At baseline, high anxious youth exhibited heightened sensitivity to GUA coupled with reduced sensitivity to PEA, as well as a further exaggeration of this bias with acute stress. Importantly, sex, age, and hedonic valence moderated the relationship between trait anxiety and sensitivity to both odorants. Smell function and its aberrations are often overlooked in the literature on biomarkers of stress and anxiety. Taken together with the extant literature, these findings suggest that greater attention is warranted to characterize potential novel olfactory therapeutic targets-across the lifespan.

Review: Exteroceptive Sensory Abnormalities in Childhood and Adolescent Anxiety and Obsessive-Compulsive Disorder: A Critical Review.

OBJECTIVE: Childhood anxiety and obsessive-compulsive disorder (OCD) are defined by fear, worry, and uncertainty, but there is also evidence that affected children possess exteroceptive sensory abnormalities. These sensory features may often instigate symptoms and cause significant distress and functional impairment. In addition, a purported class of conditions known as "sensory processing disorders" may significantly overlap with childhood anxiety and OCD, which provides further support for a connection between abnormal sensation and fear-based psychopathology. METHOD: The current review was conducted to synthesize and to critically evaluate the existing research on exteroceptive sensory abnormalities in childhood anxiety and OCD. Because of the paucity of research in this area, studies with adult populations were also briefly reviewed. RESULTS: The review found significant support for the notion that sensory abnormalities are common in children with anxiety disorders and OCD, but there are significant limitations to research in this area that prevent firm conclusions. CONCLUSION: Potential avenues for future research on sensory features of pediatric anxiety and OCD are discussed.

Exploratory Investigation of a Brief Cognitive Behavioral Intervention and Transcranial Direct Current Stimulation on Odor Sensitivity.

OBJECTIVE: Enhanced odor sensitivity is a phenomenon that potentially underlies conditions such as multiple chemical sensitivity (MCS). Currently, there are no treatments that have been shown to effectively decrease odor sensitivity. Given similarities of odor hypersensitivity/MCS to pain sensitization disorders such as fibromyalgia, there may be a potential for interventions that improve pain tolerance to modulate odor sensitivity. METHODS: This exploratory study randomized 72 healthy community adult volunteers to receive one of six treatments in between two assessments of thermal pain tolerance and odor threshold. Participants were randomized to receive either cathodal, anodal, or sham transcranial direct current stimulation (tDCS) aimed at dorsolateral prefrontal cortex. In addition, participants were provided a brief cognitive behavioral intervention (CBI) for pain consisting of task framing, cognitive restructuring, and distraction technique training, or a control intervention consisting of information about pain. RESULTS: Persons who received a brief CBI showed significantly increased odor thresholds (reduced sensitivity) during intervention (F (1,62) = 7.29, p = .009, ηp = .11), whereas the control intervention was not associated with altered odor thresholds. Moreover, in those who received brief CBI, more severe anxiety associated with larger reductions in odor sensitivity (ρ = .364, p = .035). There was no effect of tDCS (F (2,62) = .11, p = .90) nor interaction between tDCS and CBI (F (2,62) = .32, p = .73). CONCLUSIONS: Given the connection between anxiety and MCS, results suggest that CBT techniques for somatic processes may show promise in treating conditions characterized by increased sensitivity to odors (e.g., MCS).

Odor sensitivity impairment: a behavioral marker of psychological distress?

OBJECTIVE: Enhanced odor sensitivity, particularly toward threat-related cues, may be adaptive during periods of danger. Research also suggests that chronic psychological distress may lead to functional changes in the olfactory system that cause heightened sensitivity to odors. Yet, the association between self-reported odor sensitivity, objective odor detection, and affective psychopathology is currently unclear, and research suggests that persons with affective problems may only be sensitive to specific, threat-related odors. METHODS: The current study compared adults with self-reported odor sensitivity that was described as functionally impairing (OSI; n = 32) to those who reported odor sensitivity that was non-impairing (OS; n = 17) on affective variables as well as quantitative odor detection. RESULTS: Increased anxiety sensitivity, trait anxiety, depression, and life stress, even while controlling for comorbid anxiety and depressive disorders, was found for OSI compared to OS. While OSI, compared to OS, demonstrated only a trend increase in objective odor detection of a smoke-like, but not rose-like, odor, further analysis revealed that increased detection of that smoke-like odor was positively correlated with anxiety sensitivity. CONCLUSION: These findings suggest that persons with various forms of psychological distress may find themselves significantly impaired by an intolerance of odors, but that self-reported odor sensitivity does not necessarily relate to enhanced odor detection ability. However, increased sensitivity to a smoke-like odor appears to be associated with sensitivity to aversive anxiogenic stimuli. Implications for the pathophysiology of fear- and anxiety-related disorders are discussed.

Paradoxical olfactory function in combat veterans: The role of PTSD and odor factors.

Stress- and trauma-related disorders, including posttraumatic stress disorder (PTSD), are characterized by an increased sensitivity to threat cues. Given that threat detection is a critical function of olfaction and that combat trauma is commonly associated with burning odors, we sought a better understanding of general olfactory function as well as response to specific trauma-related (i.e. burning) odors in combat-related PTSD. Trauma-exposed combat veterans with (N = 22) and without (N = 25) PTSD were assessed for general and specific odor sensitivities using a variety of tools. Both groups had similar general odor detection thresholds. However, the combat veterans with PTSD, compared to combat veterans with comparable trauma exposure, but without PTSD, had increased ratings of odor intensity, negative valence, and odor-triggered PTSD symptoms, along with a blunted heart rate in response to burning rubber odor. These findings are discussed within the context of healthy versus pathological changes in olfactory processing that occur over time after psychological trauma.

Preliminary evidence for differential olfactory and trigeminal processing in combat veterans with and without PTSD.

Structural and functional changes in the olfactory system are increasingly implicated in the expression of PTSD. Still, very little is known about the neurobiological networks of trauma-related odor sensitivity or how they relate to other objective and subjective measures of olfaction and PTSD. The purpose of this study was to replicate prior findings and further characterize olfactory function in trauma-exposed combat veterans with and without PTSD. We also sought to extend this area of research by exploring the effects of time since the combat-related index trauma (TST) on post-trauma olfactory function, as well as by correlating odor-elicited brain activity to general olfactory ability and odor-elicited PTSD symptoms. Participants included combat veterans with PTSD (CV+PTSD; n = 21) or without any psychiatric disorder (CV-PTSD; n = 27). TST was coded as greater (n = 24) or less (n = 24) than 5 years. There were main effects and/or interaction for PTSD-status and TST across several parameters of olfactory function: odor detection, odor identification, ratings for trauma-related odor intensity and triggered PTSD symptoms, and trauma odor-elicited brain activation. Overall, results suggest olfactory impairment in chronic PTSD, but not necessarily in the earlier stages of the disorder, although some early-stage olfactory findings may be predictive of later olfactory impairment. Results also suggest that trauma-exposed individuals who never develop PTSD may demonstrate olfactory resiliency. Finally, results highlight a potentially unique role of trigeminal odor properties in the olfactory-PTSD relationship.

An examination of sleep quality in veterans with a dual diagnosis of PTSD and severe mental illness.

Poor sleep quality is one of the most frequently reported symptoms by veterans with Posttraumatic Stress Disorder (PTSD) and by veterans with severe mental illness (SMI; i.e., schizophrenia spectrum disorders, bipolar disorder, major depression with or without psychotic features). However, little is known about the compounding effects of co-occurring PTSD/SMI on sleep quality in this population. Given the high rates of comorbidity and poor functional outcomes associated with sleep dysfunction, there is a need to better understand patterns of poor sleep quality in this population. The present study provides a description of sleep quality in veterans with a dual diagnosis of PTSD/SMI relative to veterans with PTSD only. Results indicated that, despite similar reports of PTSD symptom severity between the groups, veterans with PTSD/SMI reported higher levels of poor sleep quality than veterans only diagnosed with PTSD. Specifically, veterans with PTSD/SMI reported significantly greater difficulties with sleep onset and overall more sleep disturbance than their non-SMI counterparts. Implications of the findings are discussed within the context of an existing model of insomnia and suggest that more comprehensive sleep assessment and the provision of targeted sleep interventions may be helpful for those with a dual diagnosis of PTSD/SMI.

Depression-Specific Outcomes After Treatment of Chronic Rhinosinusitis.

IMPORTANCE: Depression is frequently undiagnosed in patients with chronic rhinosinusitis (CRS) and affects quality of life, productivity, and health care use. OBJECTIVE: To examine depression-specific outcomes after medical or surgical treatment of CRS. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional, prospective study of patients with refractory CRS treated at tertiary academic rhinology centers was performed from March 1, 2011, to November 1, 2015. Data analysis was performed from October 1, 2015, to November 1, 2015. INTERVENTIONS: Patients self-selected to undergo continued medical management or endoscopic sinus surgery for refractory CRS. MAIN OUTCOMES AND MEASURES: Patients completed the 22-item Sinonasal Outcome Test (SNOT22), Rhinosinusitis Disability Index (RSDI), Pittsburgh Sleep Quality Index (PSQI), and missed productivity and medication use questionnaires before and at least 6 months after treatment. Computed tomography and endoscopy scoring were performed with reviewers masked to patient-reported data. Depression-specific outcomes were recorded using the 2-item Patient Health Questionnaire (PHQ2). RESULTS: Baseline data were available on 685 patients, with 167 (24.4%) having depression according to the PHQ2 scores. The mean (SD) age of the patients was 50.5 (15.0) years, and 332 (48.4%) were male. Revision surgery status was the only baseline factor associated with depression (53.9% vs 38.0%, P < .001). Patients with depression had worse baseline SNOT22 (mean, 64.5 vs 47.6), PSQI (mean, 12.8 vs 8.4), productivity (mean, 22.8 vs 5.2 days missed), and medication use scores for oral antibiotics (mean, 23.8 vs 14.8) and oral corticosteroids (mean, 17.8 vs 9.9) (P < .001 for all). Medical and surgical treatments had similar outcomes for patients with depression with mean improvement in the PHQ2 scores from 3.96 to 1.91 (P < .001), and 110 of 167 patients (65.9%) categorized as having depression at baseline were categorized as not having depression after treatment. Improvements in the PHQ2 scores were associated with improvements in the SNOT22, PSQI, oral antibiotic use, and productivity scores (P ≤ .001 for all). CONCLUSIONS AND RELEVANCE: Depression is a common comorbidity in patients with CRS and affects numerous quality-of-life and health care outcomes. There are few objective baseline factors to aid physicians in identifying depression in patients with CRS. Medical and surgical treatments for CRS improve depression and related clinical outcomes.

Depression in chronic rhinosinusitis: A controlled cohort study.

BACKGROUND: Depression in patients with chronic rhinosinusitis (CRS) is underdiagnosed but significantly impacts treatment outcomes and health care utilization. OBJECTIVE: To compare undiagnosed depression in a CRS cohort with a healthy, non-CRS control cohort. METHODS: A case-control study of patients with symptomatic CRS and a non-CRS control cohort was performed. Demographic and comorbidity factors were correlated to depression-specific outcomes by using the Beck Depression Inventory II (BDI). RESULTS: We enrolled 42 patients with CRS and 88 control patients with no history of CRS. Physician-diagnosed depression was equivalent in CRS and control patients (6% and 9%, respectively). BDI-detected depression was higher among patients with CRS compared with controls (31% versus 14.8%, respectively; p = 0.031). BDI scores were higher in patients with CRS even when controlling for comorbid asthma, allergy, and aspirin sensitivity. When examined by polyp status, the patients without polyps had more depression than did the controls (38% versus 14.8%; p = 0.048). The somatic subscale scores of the BDI were worse in patients with CRS (p = 0.004), whereas the cognitive subscale trended toward significance (p = 0.081). CONCLUSION: Depression may be more common in CRS than previously recognized, especially in patients without polyps. Somatic subscale scores of the BDI are increased in CRS and may impact future treatment outcomes.

Burning odor-elicited anxiety in OEF/OIF combat veterans: Inverse relationship to gray matter volume in olfactory cortex.

Despite the anatomical overlap between the brain's fear/threat and olfactory systems, a very limited number of investigations have considered the role of odors and the central olfactory system in the pathophysiology of PTSD. The goal of the present study was to assess structural differences in primary and secondary olfactory cortex between combat veterans with and without PTSD (CV + PTSD, CV-PTSD, respectively). An additional goal was to determine the relationship between gray matter volume (GMV) in olfactory cortex and the distressing properties of burning-related odors. A region of interest voxel-based morphometric (VBM) approach was used to measure GMV in olfactory cortex in a well-characterized group of CV + PTSD (n = 20) and CV-PTSD (n = 25). Prior to the MRI exam, combat-related (i.e., burning rubber) and control odors were systematically sampled and rated according to their potential for eliciting PTSD symptoms. Results showed that CV + PTSD exhibited significantly reduced GMV in anterior piriform (primary olfactory) and orbitofrontal (secondary olfactory) cortices compared to CV-PTSD (both p < .01). For the entire group, GMV in bilateral anterior piriform cortex was inversely related to burning rubber odor-elicited memories of trauma (p < .05). GMV in orbitofrontal cortex was inversely related to both clinical and laboratory measures of PTSD symptoms (all p < .05). In addition to replicating an established inverse relationship between GMV in anxiety-associated brain structures and PTSD symptomatology, the present study extends those findings by being the first report of volumetric decreases in olfactory cortex that are inversely related to odor-elicited PTSD symptoms. Potential mechanisms underlying these findings are discussed.

The fMRI BOLD response to unisensory and multisensory smoking cues in nicotine-dependent adults.

Given that the vast majority of functional magnetic resonance imaging (fMRI) studies of drug cue reactivity use unisensory visual cues, but that multisensory cues may elicit greater craving-related brain responses, the current study sought to compare the fMRI BOLD response to unisensory visual and multisensory, visual plus odor, smoking cues in 17 nicotine-dependent adult cigarette smokers. Brain activation to smoking-related, compared to neutral, pictures was assessed under cigarette smoke and odorless odor conditions. While smoking pictures elicited a pattern of activation consistent with the addiction literature, the multisensory (odor+picture) smoking cues elicited significantly greater and more widespread activation in mainly frontal and temporal regions. BOLD signal elicited by the multisensory, but not unisensory cues, was significantly related to participants' level of control over craving as well. Results demonstrated that the co-presentation of cigarette smoke odor with smoking-related visual cues, compared to the visual cues alone, elicited greater levels of craving-related brain activation in key regions implicated in reward. These preliminary findings support future research aimed at a better understanding of multisensory integration of drug cues and craving.

Differential odor sensitivity in PTSD: Implications for treatment and future research.

BACKGROUND: Given that odors enhance the retrieval of autobiographical memories, induce physiological arousal, and trigger trauma-related flashbacks, it is reasonable to hypothesize that odors play a significant role in the pathophysiology of posttraumatic stress disorder (PTSD). For these reasons, this preliminary study sought to examine self-reported, odor-elicited distress in PTSD. METHODS: Combat veterans with (N=30) and without (N=22) PTSD and healthy controls (HC: N=21), completed an olfactory questionnaire that provided information on the hedonic valence of odors as well as their ability to elicit distress or relaxation. RESULTS: Two main findings were revealed: Compared to HC, CV+PTSD, but not CV-PTSD, reported a higher prevalence of distress to a limited number of select odors that included fuel (p=.004), blood (p=.02), gunpowder (p=.03), and burning hair (p=.02). In contrast to this increased sensitivity, a blunting effect was reported by both groups of veterans compared to HC that revealed lower rates of distress and relaxation in response to negative hedonic odors (p=.03) and positive hedonic odors (p<.001), respectively. LIMITATIONS: The study is limited by its use of retrospective survey methods, whereas future investigations would benefit from laboratory measures taken prior, during, and after deployment. CONCLUSION: The present findings suggest a complex role of olfaction in the biological functions of threat detection. Several theoretical models are discussed. One possible explanation for increased sensitivity to select odors with decreased sensitivity to other odors is the co-occurrence of attentional bias toward threat odors with selective ignoring of distractor odors. Working together, these processes may optimize survival.

Olfactory cue reactivity in nicotine-dependent adult smokers.

Cue-elicited reactivity is a significant factor in relapse during smoking quit attempts. Previous research has focused primarily on visual smoking cues, with very limited research examining reactivity to olfactory triggers. Twenty-six adult non-treatment-seeking, nicotine-dependent smokers were exposed to 7 odorants during a cue-reactivity session measuring heart rate, skin conductance, and subjective craving. Cues included 2 cigarette odors (fresh tobacco and cigarette smoke), 2 odors previously identified as smoking-related (freshly mowed grass and coffee), 2 odors previously identified as unrelated to smoking (lavender and burned rubber), and 1 odorless control (propylene glycol). Pairwise comparisons demonstrated that subjective intensity of craving was significantly higher following exposure to the fresh tobacco odor compared with the odorless control (p < .01). A significant main effect for cue type on a physiological measure of arousal was also revealed, with a fresh tobacco odor-elicited significant increase in skin conductance level compared with the odorless control. However, no main effect of cue type on heart rate was found (p = .25). The results of the present study indicate that cigarette odor is an effective olfactory cue that heightens both subjective craving and increases skin conductance in smokers. Future research is needed to evaluate whether avoidance of these odors, or extinction of responses to them, can reduce relapse risk during smoking quit attempts.

Visual cortex activation to drug cues: a meta-analysis of functional neuroimaging papers in addiction and substance abuse literature.

BACKGROUND: Although the visual cortex does not typically receive much attention in addiction literature, neuroimaging studies often report significant activity in visual areas when drug users are exposed to drug cues. The purpose of this meta-analysis was to investigate the frequency with which occipital cortex activity is observed during drug cue exposure and to determine its spatial distribution. METHODS: A comprehensive literature search was performed of human functional neuroimaging studies of drug cue-reactivity. Fifty-five studies were used to determine the frequency with which clusters of significant visual cortex activity during visual drug cues versus non-drug cues were reported. The spatial distribution of visual cortex activations was determined via activation likelihood estimation (ALE; FDR corrected, p<0.01) in a subset of these studies (n=24). RESULTS: Eighty-six percent of studies that reported fMRI results for drug versus neutral visual cues within a substance-dependent group showed significant drug-elicited activity in the visual cortex. ALE revealed clusters in the left secondary visual cortex (BA 19) and clusters in the primary visual cortex (BA 17) that were consistently activated by drug cues. CONCLUSIONS: These data demonstrate that the visual cortex, often overlooked in our discussions of the neural circuitry of addiction, consistently discriminates drug cues from neutral cues in substance dependent populations. While it remains unclear whether drug cue-elicited activation in occipital cortex is related to the rewarding properties of the drug and/or attentional mechanisms, these data support further exploration.

Region-specific alteration in brain glutamate: possible relationship to risk-taking behavior.

Risk-taking behaviors involve increased motor activity and reduced anxiety in humans. Total sleep deprivation (SD) in animals produces a similar change in motor and fear behaviors. Investigators studied region-specific brain levels of glutamate in rats after TSD, an animal model of risk-taking behavior. We investigated the effects of sleep deprivation on these behaviors and associated levels of brain glutamate. Compared to the controls, the sleep-deprived rats spent a significantly greater percentage of time in the open arms of the elevated plus maze (EPM), demonstrating reduced fear-like and increased risk-taking behaviors. Additionally, sleep deprivation was associated with a significant increase in glutamate levels in the hippocampus and thalamus. An inverse relationship between glutamate in the medial prefrontal cortex and risk taking in the EPM and a positive association between the ratio of glutamate in the hippocampus to medial prefrontal cortex and risk taking was revealed. The role of sleep deprivation-induced changes in brain glutamate and its relationship to anxiety, fear, and posttraumatic stress disorder (PTSD) is discussed.

Anxiety and sleep problems: emerging concepts and theoretical treatment implications.

The high prevalence and comorbidity of anxiety and sleep problems, especially insomnia, suggest an important underlying relationship between these disorders. In this article, we highlight two theoretical models explaining this co-occurrence, provide a brief update on the association between anxiety-insomnia and anxiety-cataplexy in general, and review more specifically sleep problems in generalized anxiety, post-traumatic stress disorder, and panic disorder. We also explore sleep paralysis as an anxiety-sleep event. Our goal with this examination of selective anxiety-sleep problems is to provide clues about diagnostic and treatment approaches and frame strategies for future research.

Cataplexy in anxious patients: is subclinical narcolepsy underrecognized in anxiety disorders?

OBJECTIVE: Excessive daytime sleepiness, hypnagogic-hypnopompic hallucinations, sleep paralysis, and cataplexy are symptoms associated with narcolepsy. Recent findings indicate that anxiety disorders also are associated with excessive daytime sleepiness, hypnagogic-hypnopompic hallucinations, and sleep paralysis. These observations suggest a possible relationship between anxiety disorders and narcolepsy. Cataplexy is considered the most specific symptom of narcolepsy, but its association with anxiety disorders is unknown. This preliminary investigation examined the prevalence and types of cataplexy in patients with primary anxiety disorders. METHOD: Sex- and age-matched patients with anxiety disorders (N = 33) and healthy volunteers (N = 33) were assessed on standardized and validated measures of subjective sleep quality (Pittsburgh Sleep Quality Index) and subclinical narcoleptic events in the form of cataplexy (Stanford Center for Narcolepsy Revised Sleep Inventory). Patients were recruited from October 2006 to January 2007 from 2 programs of the Penn State Behavioral Health Clinic. RESULTS: Anxiety disorder patients as a group reported poorer sleep quality and endorsed a larger number of different types of situations (e.g., surprise, embarrassment) associated with cataplectic events. Among anxious patients, 33.3% (11 of 33) endorsed events specific for classic cataplexy, as opposed to 9.1% (3 of 33) of healthy volunteers (chi(2) = 5.80, p = .016). CONCLUSIONS: Our preliminary findings suggest that anxiety disorders are associated with increased rates of cataplexy. Future research is indicated to elucidate the relationship between anxiety and narcolepsy, with a particular focus on panic and generalized anxiety disorders.

A longitudinal study of the effects of lithium treatment on prefrontal and subgenual prefrontal gray matter volume in treatment-responsive bipolar disorder patients.

OBJECTIVE: Recent molecular, preclinical, and preliminary clinical studies suggest that the therapeutic effects of mood stabilizers may be mediated by modulating expression of potent neurotrophic and neuroprotective factors having the potential to reverse impairments of cellular resilience, reductions in brain volume, and cell death or atrophy. Our main goal was to investigate the potential clinical significance of these findings in relation to bipolar disorder. METHOD: The longitudinal effect of lithium on brain gray matter volume was investigated in well-characterized (DSM-IV criteria) bipolar depressed subjects (N = 28) at baseline (medication-free) and after lithium administration (4 weeks). Total brain gray matter, prefrontal gray matter, and left subgenual prefrontal gray matter volumes were determined using validated semiautomated segmentation and region of interest methodology. The study was conducted from November 1997 until April 2004 at Wayne State University School of Medicine, Detroit, Mich. RESULTS: Significant increases in total brain gray matter volume in bipolar subjects were observed after 4 weeks of lithium administration (p = .0043). Moreover, regional analyses in the bipolar subjects revealed significant differences between responders (>50% decrease in Hamilton Depression Rating Scale total score) and nonresponders; only responders showed a significant increase in gray matter volume in the prefrontal cortex (p = .003) and an increase at trend level in the left subgenual prefrontal cortex volume (p = .0786). CONCLUSION: The increase in gray matter volume in these areas, which various neuroimaging and postmortem neuropathology studies have implicated in the neuropathophysiology of bipolar disorder, suggests that the observed effects may be linked to clinical response. The findings also support the notion that future treatments that more directly target molecules in critical central nervous system pathways that regulate cellular plasticity hold promise as novel, improved, long-term treatments for mood disorders as well as some neurodegenerative conditions, such as Alzheimer's disease. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00870311.

Magnetic resonance and spectroscopic imaging in prenatal alcohol-exposed children: preliminary findings in the caudate nucleus.

Magnetic resonance imaging (MRI) and magnetic resonance spectroscopic imaging (MRSI) offer unique, noninvasive methods of measuring, respectively, in vivo quantitative neuroanatomy and neurochemistry. The main purpose of the present study was to identify and compare the neuroanatomical and neurochemical abnormalities that are associated with prenatal exposure to alcohol in both fetal alcohol syndrome (FAS)-diagnosed children and those diagnosed with fetal alcohol effects (FAE). MR data of three age-, gender- and race-balanced groups of children, FAS-diagnosed, FAE-diagnosed and non-exposed controls, were compared. Effects of prenatal alcohol exposure, regardless of diagnosis, were found in the caudate nucleus. Specifically, a significantly smaller caudate nucleus was found for the FAS and FAE participants compared to the controls. In addition, the metabolite ratio of N-acetyl-aspartate to creatine (NAA/Cr), an indicator of neuronal function, in left caudate nucleus of both the FAS and FAE participants was elevated compared to the control group. Analysis of absolute concentrations revealed that the increase in the ratio of NAA/Cr was due to an increase in NAA alone. Although its exact function in the CNS is unknown, NAA is believed to be a neuronal marker due to its exclusive localization to neurons. Some also speculate a role for NAA in myelination. Elevated NAA in the prenatal alcohol-exposed participants could indicate a lack of normal program cell death, dendritic pruning and/or myelination during development. The present study demonstrates that prenatal alcohol-exposed children, with or without facial dysmorphology, have abnormal brain anatomy and chemistry.