Frontal and temporal cortical thinning may predict increased vulnerability to development of adolescent depression. In the NCANDA sample of 692 adolescents without a history of depression, the 101 youth who transitioned into depression were found at study baseline to have thinner cortices in the superior frontal cortex, precentral and postcentral regions, and superior temporal cortex, beyond effects attributable to age and sex.Childhood trauma and post-traumatic stress symptoms have been shown to confer increased risk for adolescent and adulthood AUD, mental illness, and physical health problems.Youth with trauma exposure showed thinner frontal cortices, and those with chronic post-traumatic stress disorder had smaller orbital frontal cortices and less superior posterior cortical and cerebellar gray matter volume.These observations indicate that trauma may be associated with structural brain aberrations. NCANDA has also examined the relationship between childhood trauma and subsequent adolescent alcohol use.In a sample of 392 NCANDA participants, adverse childhood event history was linked to greater self-reported executive dysfunction spanning four annual follow-ups. Greater childhood trauma also was linked to less connectivity in sensorimotor and cognitive control networks at baseline. This reduced connectivity explained the relationship between executive dyscontrol and subsequent increased frequency of adolescent binge drinking.Sleep patterns change substantially during adolescence and emerging adulthood.Lack of sleep, going to sleep relatively late,garden racks wholesale and large weekend-weekday sleep differences all are risk factors for alcohol use in adolescents and young adults.Similarly, in the NCANDA sample, sleep difficulties in adolescence predicted later substance use problems.

The reverse has also been seen, with acute and chronic alcohol intake altering sleep structure and electroencephalography patterns in older adolescents and adults.NCANDA will continue to longitudinally examine whether these changes remain evident into adulthood and how alcohol use influences sleep neurobiology.For example, during a spatial working memory task, adolescents with co-occurring AUD and cannabis use disorder showed less inferior frontal and temporal neural activation but a greater medial frontal response compared to adolescents with AUD alone.Couse of alcohol with cannabis also may adversely influence executive functioning.Given the high rates of co-occurring alcohol and other substance use during adolescence,future well-powered studies will benefit from detailed analyses of various combinations of substances of abuse on neural and neurocognitive outcomes. In adults with AUD, improvements in attention and concentration, reaction time, and memory are generally seen after 2 to 8 weeks of abstinence;however, executive functioning, processing speed, visuospatial, and verbal skills appear more resistant to recovery,and spatial processing deficits may persist for years.Younger adults tend to recover more quickly and completely than older adults.As mentioned previously, preliminary evidence suggested that adolescent heavy drinkers showed greater response to alcohol cues,more emotional reactivity and poorer distress tolerance,and poorer visuospatial performance compared with adults. These effects remitted after a month of abstinence, indicating that some deficits are linked to alcohol intake and may be transitory. However, executive dysfunction81 and negative mood states did not remit within 4 weeks of abstinence, suggesting that these differences may have predated the onset of heavy drinking or may take more time to recover. As reported by Infante et al., cortical gray matter volume decreases were greater in proximity to reported drinking episodes in a doseresponse manner, suggesting a causal effect and raising the possibility that normal growth trajectories may recover with alcohol abstinence.

However, other studies have suggested that impaired visuospatial functioning following adolescent AUD persisted even after reduced levels of use.Longitudinal studies with large, diverse, representative samples of youth and a range of detailed measures are key to helping understand the behaviors that convey disadvantages to adolescent and young adult development and outcomes. To date, a handful of large-scale multisite studies are being conducted to gain insight into the consequences of adolescents transitioning into and out of substance use. These include the largest longterm study of brain development in the United States, the Adolescent Brain Cognitive Development Study, which is currently underway; NCANDA; the IMAGEN study in Europe; the Pediatric Imaging, Neurocognition, and Genetics study; and the Lifespan Human Connectome Project study. NCANDA has already been able to confirm impressions from prior smaller studies that adolescent heavy drinking appears linked to accelerated gray matter decline,disrupted functional connectivity,and reduced cognitive performance. Determining the degree to which these effects remit or persist with alcohol abstinence or reduced use will be a key next step in this line of work.The exact pathophysiology and aetiology of the severe mental disorders schizophrenia and bipolar disorder remain unknown. They have been hypothesized to be part of the same psychosis continuum, since they in addition to overlapping symptoms share some genetic underpinnings , cognitive impairments and brain anatomical abnormalities. Whereas pre- and perinatal complications have been established as risk factors for schizophrenia , the evidence for an association between pre- and perinatal adversities and the risk for bipolar disorder is less consistent. Some authors have argued that in genetically susceptible individuals, the absence of pre- and perinatal complications favours the development of bipolar disorder whereas their presence favours the development of schizophrenia. Nevertheless, some epidemiological studies suggest that pre- and perinatal factors may increase the risk for bipolar disorder and affective psychosis.

Hultman et al. have demonstrated an association between specific obstetric complications and affective psychosis; an increasing birth weight was found to linearly associate with decreased risk for affective disorders ; recently, increased risk for bipolar disorder in children born pre-term [odds ratio 2.7, 95% confidence interval 1.6–4.5] was reported. Accordingly, neurodevelopmental disturbances and/or pre- and perinatal trauma may also be of importance for the development of bipolar disorder. Magnetic resonance imaging studies have demonstrated the existence of neuroanatomical abnormalities in bipolar disorder , the most consistent finding being enlarged ventricular volumes. The results for other brain structures differ among studies,hydroponic racks possibly due to low sample sizes and confounding factors, such as lithium medication. Recent meta-analyses report that lithium-naive patients with bipolar disorder have smaller hippocampal and amygdala volumes as compared with patients who receive lithium medication and with healthy controls. There is also some evidence supporting more pronounced brain abnormalities in patients with psychotic bipolar disorder than in patients with non-psychotic disorder. The mechanisms underlying the structural brain abnormalities observed in bipolar disorder are not completely known. Post-mortem studies have demonstrated reduced neural somal size and neuron numbers in the amygdala, and reduced number of parvalbumin- and somatostatin-expressing interneurons and reduced pyramidal cell size in the hippocampus of bipolar disorder patients. These neuronal changes may have a developmental origin, given the fact that animal models have demonstrated long-term neuronal loss in the amygdala and reduced pyramidal cell size in the hippocampus following pre- and perinatal hypoxia. Moreover, smaller hippocampal volumes and larger ventricular volumes have been demonstrated in schizophrenia patients with a history of pre- and perinatal hypoxia. Enlarged ventricles have also been observed in schizophrenia patients who suffered prolonged birth. In schizophrenia, smaller hippocampal volumes have been reported following OCs in general , and severe OCs have been reported to interact with the hypoxia regulated GRM3 gene to affect hippocampal volume. Smaller hippocampal volume and reduced grey matter have been observed in otherwise healthy subjects born very preterm. Smaller hippocampal volume has also been reported in healthy adolescents following perinatal asphyxia , and long-term reductions of the grey matter in the amygdala have been observed in children with neonatal hypoxia– ischaemia. 

Hence, it is plausible that pre- and perinatal complications affect brain structure abnormalities associated with bipolar disorder. The aim of the current study was to investigate the relationship between pre- and perinatal trauma and brain structure volumes in patients with bipolar disorder. specifically, we studied the relationship between two measures of pre/perinatal trauma [i.e. an established composite severe OCs score comprising complications occurring throughout the whole preand perinatal period , and a diagnosis of perinatal asphyxia, a distinct complication shown by animal models to cause long-term brain abnormalities ], and three brain volumes either previously reported to be associated with OCs in schizophrenia or associated with bipolar disorder. We hypothesized that perinatal asphyxia and severe OCs would be associated with smaller hippocampus and amygdala volumes, and with larger ventricular volumes, in patients with bipolar disorder, and that the associations would be stronger in those with psychotic than in those with non-psychotic disorder. This latter prediction is based on the findings of more pronounced brain abnormalities and cognitive impairments in the psychotic than non-psychotic form of bipolar disorder. In addition, psychotic bipolar disorder may be more similar to schizophrenia, a disorder in which patients with OCs show more pronounced brain abnormalities than patients without such complications. To our knowledge, this is the first study to explore the association between hypoxia-related OCs, in particular perinatal asphyxia, and neuroanatomy in bipolar disorder.We found that perinatal asphyxia and severe OCs were related to smaller amygdala and hippocampal volume in patients with bipolar disorder. Whereas patients with psychotic bipolar disorder showed reduced amygdala volume following perinatal asphyxia, patients with non-psychotic bipolar disorder showed reduced hippocampal volume following perinatal asphyxia and severe OCs, after adjustment for multiple comparisons, and controlling for the effects of age, sex, ICV and medication use. To the best of our knowledge, this is the first study to investigate associations between hypoxia-related pre- and perinatal complications and brain MRI morphometry in bipolar disorder. Our findings indicate that perinatal hypoxic brain trauma is of importance for the adult brain morphology in bipolar disorder, and may thus be a neuro developmental factor of importance to disease development. This concurs to some extent with large scale epidemiological studies that report lower birth weight , specific OCs and premature birth to increase the risk for bipolar disorder or affective psychosis. Indeed, we have in a subject sample overlapping with the current study previously demonstrated lower birth weight to correlate with smaller brain cortical surface area in patients across the psychosis spectrum as well as healthy controls. The results from the current study expand on this by demonstrating distinct associations between specific hypoxia-related pre- and perinatal complications and sub-cortical structures, known to be vulnerable to perinatal hypoxia ,in patients with bipolar disorder. As such, the current findings to some extent support the speculation by Nosarti et al. that there may exist a neurodevelopmental subtype of bipolar disorder. Within the whole group of bipolar disorder patients, we found perinatal asphyxia to be significantly associated with smaller left amygdala volume. The amygdala is involved in emotion processing and regulation, disturbances of which are core features of bipolar disorder. Altered amygdala function related to emotion-processing tasks has repeatedly been reported from functional MRI studies in patients with bipolar disorder. Emotional dysregulation and impaired stress response, other important features of bipolar disorder , may be caused by disturbances in corticotropin metabolism and dysfunction in the hypothalamic–pituitary–adrenal axis. Interestingly, a recent rat model study demonstrated significant long-term loss, shrinkage of cell soma size, and axonal degeneration of corticotropin-releasing factor-positive neurons in the amygdala following neonatal hypoxia–ischaemia. These changes were associated with increased locomotor activity and exploratory behaviour , behavioural abnormalities that are also observed in patients with bipolar disorder. Moreover, increased anxiety has been reported following perinatal asphyxia and is associated with dopamine-innervated neurocircuitries in the amygdala, among other structures. Dopaminergic pathways are particularly vulnerable to perinatal asphyxia , and are also involved in the pathophysiology of psychotic disorders. Taken together, it seems biologically plausible that perinatal asphyxia is associated with long-term alterations in the structure of the amygdala, as our results suggest. Such alterations may be functionally associated with the distinct behavioural abnormalities observed in bipolar disorder. Instead of confirming our initial hypothesis that the associations between perinatal asphyxia/severe OCs would be stronger in patients with psychotic than non-psychotic bipolar disorder, the results indicate different patterns of associations in psychotic versus non-psychotic bipolar disorder. Within a psychosis continuum, psychotic bipolar disorder would be considered to be closer than non-psychotic bipolar disorder to schizophrenia. In schizophrenia, smaller hippocampal volumes have been associated with preand perinatal trauma. Surprisingly, we found no associations between severe OCs or perinatal asphyxia and smaller hippocampal volume in patients with psychotic bipolar disorder, but we did find such associations in patients with non-psychotic bipolar disorder. The biological validity of this association is, nevertheless, supported by the literature. First, animal models have demonstrated the pyramidal neurons within the hippocampus to be sensitive to prenatal hypoxia. Second, in the human neonate, hippocampal neurocircuitries are reported to be particularly vulnerable to hypoxia , and, third, healthy adolescents who have suffered perinatal asphyxia exhibit reduced hippocampal volumes.