By the time psychosis appears in someone with schizophrenia, biological changes associated with the illness may have already been present for years. A 2015 article by R.S. Kahn and I.E. Sommer in the journal Molecular Psychiatry describes some of these abnormalities and how treatments might better target them.
One such change is in brain volume. At the time of diagnosis, schizophrenia patients have a lower intracranial volume on average than healthy people. Brain growth stops around age 13, suggesting that reduced brain growth in people with schizophrenia occurs before that age.
At diagnosis, patients with schizophrenia show decrements in both white and grey matter in the brain. Grey matter volume tends to decrease further in these patients over time, while white matter volume remains stable or can even increase.
Overproduction of dopamine in the striatum is another abnormality seen in the brains of schizophrenia patients at the time of diagnosis.
Possibly years before the dopamine abnormalities are observed, underfunctioning of the NMDA receptor and low-grade brain inflammation occur. These may be linked to cognitive impairment and negative symptoms of schizophrenia such as social withdrawal or apathy, suggesting that there is an at-risk period before psychosis appears when these symptoms can be identified and addressed. Psychosocial treatments such as individual, group, or family psychotherapy and omega-3 fatty acid supplementation have both been shown to decrease the rate of conversion from early symptoms to full-blown psychosis.
Using antipsychotic drugs to treat the dopamine abnormalities is generally successful in patients in their first episode of schizophrenia. Use of atypical antipsychotics is associated with less brain volume loss than use of the older typical antipsychotics. Treatments to correct the NMDA receptor abnormalities and brain inflammation, however, are only modestly effective. (Though there are data to support the effectiveness of the antioxidant n-acetylcysteine (NAC) on negative symptoms compared to placebo.) Kahn and Sommer suggest that applying treatments when cognitive and social function begin to be impaired (rather than waiting until psychosis appears) could make them more effective.
The authors also suggest that more postmortem brain analyses, neuroimaging studies, animal studies, and studies of treatments’ effects on brain abnormalities are all needed to clarify the causes of the early brain changes that occur in schizophrenia and identify ways of treating and preventing them.
At the 2015 meeting of the International Society for Bipolar Disorders, Ben Goldstein described a study of cognitive dysfunction in pediatric bipolar disorder. Children with bipolar disorder were three years behind in executive functioning (which covers abilities such as planning and problem-solving) and verbal memory.
There were other abnormalities. Youth with bipolar disorder had smaller amygdalas, and those with larger amygdalas recovered better. Perception of facial emotion was another area of weakness for children (and adults) with bipolar disorder. Studies show increased activity of the amygdala during facial emotion recognition tasks.
Goldstein reported that nine studies show that youth with bipolar disorder have reduced white matter integrity. This has also been observed in their relatives without bipolar disorder, suggesting that it is a sign of vulnerability to bipolar illness. This could identify children who could benefit from preemptive treatment because they are at high risk for developing bipolar disorder due to a family history of the illness.
There are some indications of increased inflammation in pediatric bipolar disorder. CRP, a protein that is a marker of inflammation, is elevated to a level equivalent to those in kids with juvenile rheumatoid arthritis before treatment (about 3 mg/L). CRP levels may be able to predict onset of depression or mania in those with minor symptoms, and is also associated with depression duration and severity. Goldstein reported that TNF-alpha, another inflammatory marker, may be elevated in children with psychosis.
Goldstein noted a study by Ghanshyam Pandey that showed that improvement in pediatric bipolar disorder was related to increases in BDNF, a protein that protects neurons. Cognitive flexibility interacted with CRP and BDNF—those with low BDNF had more cognitive impairment as their CRP increased than did those with high BDNF.
Many people suffer problems with mental functioning after an apparent concussion (otherwise known as mild traumatic brain injury, or mTBI) that does not show abnormalities on traditional brain imaging measures such as the MRI. New technology called diffusion tensor imaging (DTI) shows that the integrity of white matter tracts may be disturbed by concussions. White matter comprises parts of the brain where myelin wraps around axons, as opposed to grey matter, which reflects the presence of neuronal cell bodies.
In a longitudinal study published in the Journal of Neurotrauma, Vigneswaran Veeramuthu and colleagues compared 61 people with an mTBI to 19 healthy controls. The mTBI participants had their neuropsychological faculties assessed an average of 4.35 hours after their trauma, and participated in DTI scans an average of 10 hours after the trauma. Both the neuropsychological assessment and the DTI scan were repeated six months later. When the acute and follow-up assessments were compared to the same assessments in control participants, the two groups showed differences in numerous white matter tracts at the six-month mark. There was also an association between the degree of abnormality observed on the DTI scans and decrements in performance on the tests of neuropsychological functioning both immediately after the trauma and six months later.
The researchers concluded that their results “provide new evidence for the use of DTI as an imaging biomarker and indicator of [white matter] damage occurring in the context of mTBI, and [the results] underscore the dynamic nature of brain injury and possible biological basis of chronic neurocognitive alterations.”
Editor’s Note: People should be aware of these findings, which confirm earlier studies, and begin rehabilitative treatment as soon as possible after a concussion. New research should target white matter tract changes, with the goal of secondary prevention, i.e. limiting damage to the brain after a traumatic injury has occurred. There are several promising drugs that can prevent damage if administered immediately after an mTBI, including the antioxidant supplement N-acetylcysteine (NAC), which has shown promise in preliminary clinical and laboratory studies, and many others, including lithium and valproate, as reported by De-Maw Chuang and this editor Robert M. Post in a 2015 article in the Journal of Neurology and Stroke titled “Preventing the Sequelae of Concussions and Traumatic Brain Injury.”
Marijuana Addiction Associated with White Matter Loss and Brain Changes in Healthy People and Those with Schizophrenia
It has been established that cannabis use is associated with impairments in working memory, but researchers are still investigating how these impairments come about. A 2013 study by Matthew J. Smith et al. in the journal Schizophrenia Bulletin compared regular marijuana users both with and without schizophrenia with demographically similar people who did not use marijuana.
Using magnetic resonance imaging (MRI), the researchers were able to map each participant’s brain structures. Healthy people who were marijuana users showed deficits in white matter (axons of neurons that are wrapped in myelin) compared to healthy people who did not use the drug. Similarly, patients with schizophrenia who used marijuana regularly had less white matter than those patients with schizophrenia who did not use the drug. There were also differences in the shapes of brain structures, including the striatum, the globus pallidus, and the thalamus, between cannabis users and non-users.
Differences in the thalamus and striatum were linked to white matter deficits and to younger age of cannabis use disorder onset.
Differences between cannabis users and non-users were more dramatic across the populations with schizophrenia than across the healthy populations.
Editors note: Future research is needed to determine whether marijuana causes these brain changes, or whether the brain changes are a biomarker that shows a vulnerability to marijuana addiction (although the latter is less likely than the former).
Other data show that marijuana is associated with an increase in psychosis (with heavy use), cognitive deficits, and an earlier onset of both bipolar disorder and schizophrenia in users compared to non-users. These findings make pot begin to look like a real health hazard. With legalization of marijuana occurring in many states, ease of access will increase, possibly accompanied by more heavy use. The most consistent pharmacological effect of marijuana is to produce an amotivational syndrome, characterized by apathy or lack of interest in social activities. Particularly for those already struggling with depression, pot is not as benign a substance as it is often thought to be.
In a 2013 study of children by Luby et al. in the Journal of the American Medical Association Pediatrics, poverty in early childhood was associated with smaller white and gray matter in the cortex and with smaller volume of the amygdala and hippocampus when the children reached school age. The effects of poverty on hippocampal volume were mediated by whether the children experienced stressful life events and whether a caregiver was supportive or hostile.
The children were recruited from primary care and day care settings between the ages of three and six, and were studied for five to ten years. They were initially assessed annually for three to six years and information on psychosocial, behavioral, and developmental dimensions were collected. Then the children took part in a magnetic resonance imaging (MRI) scan and continued annual assessments that included information such as whether the children experienced stressful life events.
Previous research has shown that poverty affects children’s psychosocial development and economic success in adulthood. This research shows that poverty also affects brain development. The findings suggest important targets for intervention that could help prevent these developmental deficits.
At a recent scientific conference, researcher Donna Roybal presented research showing that children at high risk of developing bipolar disorder due to a positive family history of the illness had some abnormalities in important white matter tracts in the brain. Prior to illness onset, there was increased fractional anisotropy (FA), a sign of white matter integrity, but following the onset of full-blown bipolar illness there were decreases in FA.
Roybal postulated that these findings show an increased connectivity of brain areas prior to illness onset, but some erosion of the white matter tracts with illness progression.
Editor’s Note: It will be critical to replicate these findings in order to better define who is at highest risk for bipolar disorder so that attempts at prevention can be explored.
New research shows that regular meditation in the form of mindfulness training improves both mood and measures of white matter (axon tract) integrity and plasticity in the anterior cingulate cortex (a key node in the brain network modulating self-regulation).
This research by Tang et al. published in the Proceedings of the National Academy of Sciences in 2012 was a continuation of the same research group’s investigation of integrative mind-body training (IMBT), a type of mindfulness training that incorporates increased awareness of body, breathing, and attention to external instructions meant to induce a state of balanced relaxation and focused attention. In a previous Tang et al. study comparing participants who received IMBT training with a control group who spent the same amount of time doing relaxation training, the participants who practiced IMBT for five days (20 minutes/day) had better scores on measures of attention, anxiety, depression, anger, fatigue, and energy. In another study the researchers found that four weeks of IMBT (30 minutes/day) increased fractional anisotrophy (FA) in white matter areas involving the anterior cingulate cortex, while four weeks of relaxation training did not bring about any effect on white matter. Decrease in FA is a part of aging. The four weeks of IMBT also decreased axial and radial diffusivity, suggesting better alignment of axons along white matter tracts.
In the most recent study, two weeks of IMBT (30 minutes/day) produced a reduction in axial diffusivity, but not effects on fractional anisotrophy or radial diffusivity, suggesting that the reduced axial diffusivity leads to the other changes seen with longer IMBT.
Editor’s Note: In those with unresolved problems with anxiety and depression, regular 20-30 minutes/day mindfulness practice may have beneficial effects not only on mood, but also on central nervous system structures. Mindfulness training involves focused attention on sequentially different parts of the body leading to exclusive focus on the physical aspects of breathing in and out. Intruding thoughts are recognized, but let go as trivial, passing interruptions, and focus is returned to the body and breathing. The aim is to clear the mind of its usual ideas, thoughts, and worries by continually refocusing on breathing. It takes practice to achieve, but regular mindfulness training can be a helpful addition to pharmaco- and psychotherapy.
It is also noteworthy that mindfulness training is one of the processes that helps elongate the ends of each strand of DNA, called telomeres. Telomeres shorten with aging, stress, and episodes of depression, and short telomeres lead to a variety of adverse medical consequences.
As childhood obesity has increased over the past several decades, the metabolic syndrome has also become more prevalent among children and adolescents. The metabolic syndrome consists of five measures related to obesity: elevations in fasting glucose levels or insulin resistance, a high proportion of LDL (“bad” cholesterol) to HDL (“good” cholesterol), elevated triglycerides, hypertension, and abdominal obesity or high waist circumference. A patient with three of these abnormalities would be diagnosed with the metabolic syndrome.
In adults, the metabolic syndrome has been associated with neurocognitive impairments. Researchers decided to look at adolescents with the metabolic syndrome to determine whether these brain effects are a result of long-term metabolic impairment or whether they can take place after short-term periods of poor metabolism as well. In a study published by Yau et al. in the journal Pediatrics last year, 49 adolescents with the metabolic syndrome were compared to 62 adolescents without the syndrome who had been matched for similar age, socioeconomic status, school grade, gender, and ethnicity.
The adolescents with the metabolic syndrome had lower scores on tests of math, spelling, attention, and mental flexibility, as well as a trend for lower overall intelligence. In brain measures such as hippocampal volume, amount of brain cerebrospinal fluid, and microstructural integrity in white matter tracts, the seriousness of the metabolic syndrome correlated with the level of abnormality on these measures.
Editor’s Note: It seems as though even short-term problems with metabolism can lead to brain impairments like lower cognitive performance and decreased integrity of brain structures. These effects are even seen before vascular disease and type 2 diabetes are manifest.
It is doubly important, in terms of both cardiovascular and neurobiological risks, to look out for one’s medical and psychiatric health. Reducing the abnormal components of the metabolic syndrome should produce benefits for both the cardiovascular system and the central nervous system.
Almost 40% of patients with bipolar illness in the US have the metabolic syndrome, so considerable effort will be required to improve this public health crisis.
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Carrie E. Bearden presented data from a study that predicted conversion to psychosis in at-risk youth (those who have prodromal symptoms or a particular genetic mutation that leads to psychosis) by observing white matter abnormalities.
Bearden found that the degree of white matter abnormality seen during magnetic resonance imaging (MRI) was proportional to the degree of cognitive deficit in patients who subsequently developed a first episode of psychosis. The white matter abnormalities were seen particularly in the superior longitudinal fasciculus (SLF) and were associated with increased severity of symptomatology. The overall degree of white matter alteration was also significantly related to clinical outcome 15 months later.
Editor’s Note: The SLF is a major neuronal conduit between prefrontal cortical systems, which are responsible for cognition and planning, and the parietal cortex, which is responsible for spatial abilities. Disruption of this fiber track has been related to difficulties in social cognition and “theory of mind” concepts, like inferring what others might be thinking.
In an abstract presented at the 5th Biennial Conference of the International Society for Bipolar Disorders, K. Sim and colleagues discussed the impact of increased body mass index on the integrity of white matter in the brain during a first episode of mania. The researchers found significant abnormalities in white matter integrity in the temporal pole and occipital brain regions in overweight and obese patients compared to patients of normal weight. These data highlight the need to clarify the neural mechanisms that link obesity and poorer functional outcomes in bipolar disorder.
Other investigators have reported that bipolar patients with obesity have a less robust response to naturalistic treatment compared to those of normal weight. At least one study suggested that patients with overweight and obesity experience more cognitive difficulties.
Editor’s Note: The pathophysiological mechanisms involved in the relationship between weight and brain function are not yet clear, although one possibility is that in obese patients, some fat cells in the abdominal area become too big to survive and are scavenged by other cytokine-producing cells. These inflammatory cytokines are then able to cross the blood-brain barrier, enter the brain, and affect neuronal functioning. Whether a mechanism like this is at play in relation to these particular findings remains for further investigation.
Nonetheless, these data suggest the importance of good diet, exercise, and other means of maintaining a good body weight in order to attempt to avoid some of the adverse associations of obesity with deficits in cognition, white matter integrity, and treatment outcome.