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They examined fractional anisotropy (FA) in multiple pathways including the corpus callosum generic decaris 50mg with mastercard, thalamic radiation and inferior longitudinal fasciculus 50mg decaris otc. They demonstrated widespread myelin pathology and effects on neuronal connectivity and function buy decaris 50mg low cost. Akine et al (2007) studied a group of alcohol dependent persons (long-term abstinent) using functional MRI and mental tasks. They found reduced activation of the anterior cingulate, right dorsolateral prefrontal cortex, left pulvinar (thalamus), and right ventral striatum. Kish et al (2010) using positron emission tomography (PET) combined with MRI , studied cortical serotonin transporter density in ecstasy (MDMA) users. They found serotonin transporter density in ecstasy users was significantly reduced in all cerebral cortices, particularly in the insular and occipital cortices. Surprisingly, there was sparing of the serotonin transporter-rich striatum. Personality and substance use There is a high comorbidity of personality disorder and substance use, which increases the difficulties of management (Di Lorenzo et al, 2014). Evidence suggests that particular personality types are attracted to different substances and different patterns of substance use. Nevertheless, a broad spectrum of personality types become involved, and each individual must be considered separately. A recent meta-analysis (Malouff et al, 2007) of alcohol studies found use was associated with low conscientiousness, low agreeableness and high neuroticism. However, once substance dependence has developed, obsessional, dependent and anxious characteristics make stopping more difficult (Tyrer, 1989). Genetics and substance use Brief mention is made here; some further details are listed, when available, under separate substances. There is 50% heritability of drug use, but the genes for vulnerability are yet to be determined. Perhaps hundreds of genetic variations summate in a single individual to confer addiction (Nestler, 2013). Considering all substances, using a large twin data base, Kendler et al (2007) identified 2 genetic factors and an environmental factor. One genetic factor loaded strongly on cocaine and cannabis dependence, the other, on alcohol and nicotine dependence. A classification of alcoholism in which there are two main forms, and which may have a genetic basis, has been described (Cloninger, 1987). This classification has not been widely used, and it may or may not survive the test of time. Type I: late onset, low inheritance, associated with anxiety, often with drinking binges to relieve stress. Type II: younger age of onset, heavy regular intake, associated with antisocial personality traits and criminality. It is limited to males and may be associated with under-functioning of the serotonin system. Genetic polymorphisms of serotonin receptors and enzymes have been reported in Type II subjects (Nielsen et al, 1994). Further genetics information is given under the heading: Alcohol. A recent meta-analysis found that gene variants of the serotonin 1B receptor is associated with alcohol, cocaine, and heroin abuse (Cao et al, 2013). Epigenetics Epigenetics is a new area of enormous interest to students of human behaviour – and frequently mentioned in the Download of Psychiatry – It describes a process which changes gene expression without altering the DNA sequence. Information which has been stated elsewhere will not be repeated here. However, much of what we know of epigenetics has come from studies in substance use. Nestler (2001) showed that drug abuse can alter gene expression in the reward areas, NAc, ventral tegmental area and prefrontal cortex. Im et al (2010) reported persistent release of brain derived neurotropic factor (BDNF) in the NAc and ventral tegmental area. Kennedy et al (2013) have shown the infusion of a histone deacetylase inhibitor can prevent NAc changes. Motivations to take substances The following may be involved in the motivation to take substances. However, a two item screening test has been shown to detect 80% of young and middle-aged individuals with problems (Brown et al, 2001): 1. These items should be included in any assessment of substance use. The threshold of the at-risk category varies from one country to another, being 21 standard drinks per week in the United Kingdom, and 14 in Canada and the United States. The size of the “standard drink” is frequently misunderstood.
Healthy persons are typically aware of seeing only the neutral faces cheap decaris 50 mg overnight delivery, although they show amygdala activation to the masked fear- OBSESSIVE-COMPULSIVE DISORDER ful faces (142) order 50 mg decaris mastercard. Rauch and colleagues found greater amyg- Corticostriatal Model dala activation to masked fearful faces in persons with PTSD than in control subjects (108) cheap decaris 50 mg free shipping. Furthermore, the magnitude One current neuroanatomic model of OCD focuses on cor- of amygdala activation was correlated with PTSD severity. According to Chapter 65: Structural and Functional Imaging of Anxiety and Stress Disorders 959 this model, the primary disorder lies within the striatum as well as functional MRI (15) have also most consistently (specifically, the caudate nucleus). This leads to inefficient shown increased brain activity within anterior-lateral orbit- gating at the level of the thalamus, which results in hyperac- ofrontal cortex, anterior cingulate cortex, and caudate nu- tivity within orbitofrontal cortex (corresponding to the in- cleus during the OCD symptomatic state. In these studies, patients with OCD perform are performed to recruit the inefficient striatum ultimately an implicit (i. In both studies, patients with OCD failed to recruit stria- tum normally and instead activated medial temporal regions Structural Imaging Findings typically associated with conscious information processing. The results of several mMRI investigations of OCD have suggested volumetric abnormalities involving the caudate Imaging Studies of Neurochemistry nucleus, although the nature of the observed abnormalities has been somewhat inconsistent. Ebert and colleagues (41) found reduced in the OCD group. Glutamate is the principal transmitter mediat- mixed-gender cohort of 24 patients with OCD versus 21 ing frontostriatal communication. Interestingly, elevated matched controls and found no significant differences in striatal glutamate levels were attenuated toward normal after striatal volumes. These findings suggest that or- ment-naive pediatric subjects with OCD and 19 case- bitofrontal hyperactivity in OCD may be mirrored by ele- matched psychiatrically healthy comparison subjects. These vated glutamate at the site of orbitofrontal ramifications in investigators found reduced striatal volumes in the OCD striatum, and treatment-related attenuation of orbitofrontal group and an inverse correlation between striatal volume and OCD symptom severity. Functional Imaging Findings Neutral state paradigms employing PET and SPECT have Summary most consistently indicated that patients with OCD exhibit Taken together, these neuroimaging findings are consistent increased regional brain activity within orbitofrontal and with disorders in corticostriatothalamocortical circuitry. Observed dif- the striatum, MRI and MRS studies of OCD have shown ferences in regional activity within the caudate nucleus have been less consistent (6,113). PET studies have revealed hyperactivity within orbit- lated attenuation of abnormal regional brain activity within ofrontal cortex, and the magnitude of this hyperactivity pre- orbitofrontal cortex, anterior cingulate cortex, and caudate dicts response to treatment. In addition, in neurologically nucleus (8,9,61,95,124,137). In addition, both pharmaco- normal persons, the performance of repetitive motor rou- logic and behavioral therapies appear to be associated with tines does facilitate striatal recruitment in the service of thal- similar brain activity changes (8,124). Some treatment stud- amic gating, whereas this pattern is not readily demon- ies have also reported that lower pretreatment glucose meta- strated in patients with OCD. These imaging data further bolic rates in orbitofrontal cortex predict a better response support the working model of striatal pathology and striato- to serotonergic reuptake inhibitors (24,118,136). In comparison with the control phobias are learned and hence reflect another example of group, the SoP group exhibited hyperresponsivity within fear conditioning to specific stimuli or situations. Alterna- the amygdala that was specific to the human face stimuli. For instance, if humans have evolved a neural net- The researchers used a classic conditioning paradigm in work specifically designed to assess social cues for threaten- which neutral face stimuli were the conditioned stimuli and ing content, and another to assess threat from small animals, odors (negative odor and odorless air) served as the uncondi- these may represent the neural substrates for the pathophysi- tioned stimuli. In response to conditioned stimuli associated ology underlying phobias. Given the high prevalence of phobias and the relative ease with which medication-free phobic subjects without signifi- cant comorbidities can be recruited, it is striking how few Imaging Studies of Neurochemistry imaging studies have been conducted in this arena. Relative to the cerebrum, caudate, putamen, and thalamus in 22 patients control group, the SoP group exhibited decreased NAA in with SoP and in 22 matched healthy control subjects (96). They found significantly reduced striatal dopamine Studies of SpP to date have principally employed PET reuptake binding site density in the SoP versus control symptom provocation paradigms and have reported some- group. Mountz and colleagues found that persons with small-animal phobia exhibited increased heart rates, respiratory rates, and subjective reports of anxiety dur- Summary ing exposure to phobic stimuli; however, no changes in Although relatively few neuroimaging studies of SpP have rCBF measurements were observed (88). Although such results are consistent with a dition, they found significant rCBF increases in secondary hypersensitive system for assessment of or response to spe- visual cortex and rCBF decreases in prefrontal cortex, poste- cific threat-related cues, they do not provide clear anatomic rior cingulate cortex, anterior temporopolar cortex, and hip- substrates for the pathophysiology of SpP. These findings were similar to those of two other tion neuroimaging studies of SoP reveal exaggerated respon- studies of phobia from the same laboratory (50,51). In the provoked versus control condition, patients with phobias exhibited rCBF increases within mul- tiple anterior paralimbic territories (i. Whereas one neutral-state SPECT study of patients with Neurobiological models of PD have emphasized a wide SoP and healthy control subjects found no significant be- range of disparate elements (31). Satisfactory models of PD tween-group differences in rCBF (133), more recent cogni- must account for spontaneous panic attacks, which are a Chapter 65: Structural and Functional Imaging of Anxiety and Stress Disorders 961 defining feature of PD. It is possible that spontaneous panic inferior frontal cortex. In comparison with the untreated corresponds to a normal physiologic anxiety response that group, the imipramine-treated group exhibited rCMRglc is mediated by intact fear-anxiety circuits but, owing to decreases in posterior orbital frontal cortex.
In the study of Kemeny and Dean (197) buy 50mg decaris amex, the stress sion cut point) was noted in self-reported depressive symp- of bereavement before study entry was associated with a toms beginning 1 purchase decaris 50mg line. Bereavement did not predict authors interpreted these findings as an indication that progression to AIDS or mortality rate generic decaris 50mg visa. However, a subsequent survival analysis of these data, development of HIV-related clinical symptoms at 2-year in which the level of depressive symptoms during the 6 follow-up was greater. In a recent study of 67 asymptomatic months before AIDS diagnosis was used, showed no rela- HIV-infected African-American women, trauma (e. A death of child, assault, rape), particularly among those with limitation of both these prospective cohort studies is the posttraumatic stress disorder, was associated with a greater method of ascertainment of depression. The CES-Dis not decrease in the CD4 /CD8 ratio during 1 year of follow- a clinical diagnostic tool; its sensitivity for DSM-III major up (199). Stud- gay men who are followed every 6 months; extensive clinical ies that examine actual stressors (e. An analysis of this cohort at study entry showed a are more likely to show such results than studies based on significant effect of stress on parameters of cellular immu- questionnaire assessments of stress. These findings echo symptoms, measured by a modified Hamilton Depression those of some earlier research showing potentially harmful Rating Scale (HDRS) excluding somatic symptoms that effects of denial and potentially beneficial effects of social could be related to HIV disease. In the study of Antoni and colleagues severe depressive symptom (3-point increment on the (203), HIV-infected gay men scoring above, rather than HDRS), the risk for AIDS doubled (194). This result, how- below, the median on passive coping strategies (e. An increase in denial from before to after sero- erate the progression of HIV-1 disease. However, these stud- status notification was also associated with a greater proba- ies require confirmation by comprehensive, longitudinal in- bility of development of symptoms and AIDS during a 2- vestigations in which similar methodologies are used. In the study of study is also necessary to increase our understanding of the Solano and colleagues (201) of 100 male and female HIV- neuropsychiatric manifestations of HIV-1 infection in infected subjects, those who became symptomatic after 1 women and its special effects on neurologic development year had shown more denial and less 'fighting spirit' at in infants and children. Recent controlled trials of psychopharmacologic treat- The findings of other studies regarding the effects of ment have yielded positive results for the alleviation of social support have been less consistent. Larger social net- depression, and preliminary evidence also indicates a reduc- works and greater emotional support predicted longer sur- tion in neurocognitive impairment. Future neuropsycho- vival during 5 years in men who were symptomatic or had pharmacologic approaches will likely focus on both direct AIDS; however, larger social networks were associated with and indirect effects of HIV-1 in the brain in an effort to faster progression to AIDS in those who were asymptomatic develop novel interventions that may alter the course of at entry (202). Loneliness was associated with a more rapid disease and symptomatic treatments to improve clinical out- decline in CD4 levels but was unrelated to AIDS or mor- come and quality of life. The long-term impact of HAART tality during 3 years of follow-up in 205 symptomatic HIV- on HIV-related CNS disease and associated neuropsychia- infected men (204). Other prospective studies have reported tric manifestations will also be extensively studied. In summary, the evidence is substantial that psychosocial ACKNOWLEDGMENTS factors such as depression and stressful life events may ad- versely affect disease progression in persons infected with The authors thank Carol Roberts, B. It must be noted that most of the cited studies of tance in the preparation of this manuscript. Therefore, we need additional studies of women and patients currently on HAART. Evans has received research support from SmithKline CONCLUSION Beecham and serves as a consultant to a number of pharma- ceutical companies, including Abbott Laboratories, Eli Lilly, Considerable preclinical and clinical research has been con- Janssen Pharmaceutica, Organon, Pfizer, SmithKline Bee- ducted in an effort to describe the neuropsychiatric manifes- cham, TAP Pharmaceuticals, Wyeth-Ayerst Laboratories, tations of HIV-1 disease and increase our understanding of and Forest Laboratories. The virus en- ters the CNS early in the course of disease and causes both direct and indirect CNS effects. Subtle abnormalities can REFERENCES be detected on pathologic, neuroimaging, and neuropsycho- logical studies before the onset of AIDS-defining illnesses, 1. Geneva: World Health although the clinical significance of these findings continues Organization, 1999. Natural history of neuropsychiatric mani- to be unclear. In symptomatic AIDS, neuropsychiatric and festations of HIV disease. Psychiatr Clin North Am 1994;17: neurologic complications are prevalent, and these can often 17–33. Reduced basal Since the earliest years of the HIV epidemic, most per- ganglia volume in HIV-1-associated dementia: results from sons infected with HIV-1 have coped well. Zidovudine therapy and continues to be the most prevalent common psychiatric di- HIV encephalitis: a 10-year neuropathological survey. AIDS agnosis in HIV-1-seropositive men; the prevalence is high 1994;8:489–493. The AIDS dementia lation, but it is similar to that in seronegative gay men and complex: II. Magnetic no higher than that in patients with other serious medical resonance imaging measurement of gray matter volume reduc- illnesses. The interrelationships between the CNS, endo- tions in HIV dementia.
Early in 2008, Sue Clark brought a handful of epigenetics researchers from Australia together to form the Australian Epigenetics Alliance. The AEpiA has now grown to a membership of nearly 300, with members spanning not only Australasia, but the globe. Last year we hosted our seventh flagship conference, Epigenetics 2017 in Brisbane, QLD, and the WA team are already busy preparing for Epigenetics 2019 – watch this space!
Past Epigenetics meetings: