Top @WRY999 Neuroscience Twitter Posts: August 2016

Here are selected top Twitter posts from my @WRY999 feed for the month of August.

Follow me on Twitter by clicking HERE.

I used the Twitter analytics page to sort out the Twitter posts with the most impressions and engagements for August of 2016.

Photos from the trip to Santa Fe, New Mexico were popular and I have included the top photo of a Santa Fe sunset. This photo was taken from the Cross of the Martyrs park .

"Jump starting the brain: Experimental device suggests new path to rousing coma patients" https://t.co/Uon030XRkj #science #feedly

— W.R.Yates, M.D.✍ (@WRY999) August 25, 2016

Common brain signature marks autism, attention deficit (disruption in corpus callosum)
https://t.co/2bm4EzEvwX

— W.R.Yates, M.D.✍ (@WRY999) August 8, 201

"Virtual reality and treadmill training could help prevent falls in older adults" #neuroscience #feedly https://t.co/xcEfjm5vdR

— W.R.Yates, M.D.✍ (@WRY999) August 12, 2016

"Face shape is in the genes" https://t.co/jzzng9vZN5 #neuroscience #feedly

— W.R.Yates, M.D.✍ (@WRY999) August 26, 2016

MT Some psychotic disorders may be induced by epilepsy drugs(women and temporal lobe seizures) https://t.co/r2zLHSnec8 #feedly

— W.R.Yates, M.D.✍ (@WRY999) August 9, 2016

Follow me on Twitter by clicking HERE.

Brain Default Network in Psychotic Bipolar Disorder

In a previous post I reviewed a summary of research related to genetics and improved diagnosis in bipolar disorder.

One key point in this review was a highlight of the promise for integrating genetic with imaging research in bipolar disorder and other neuropsychiatric disorders.

An example of this type of integrated research has been recently published in PNAS by a group of Yale University, the University of New Mexico and the University of Texas Southwestern Medical Center.

This study used functional magnetic resonance imaging (fMRI) default mode network (DMN) across a group of subjects with psychotic bipolar disorder, schizophrenia and healthy controls. Additionally, study included imaging a group of unaffected relatives of the psychotic bipolar subjects and schizophrenia.

Subjects also had genetic analyses available for comparison with any imaging results that would emerge in the study.

The research team identified three circuit components in the DMN. The included the networks below (also identified by color as highlighted in group name):
Anterior DMN--Medial prefrontal cortex-anterior cingulate caudate DMN
Inferior posterior DMN--posterior cingulate caudate, inferior parietal lobule, middle temporal gyrus, cuneus/pre-cuneus
Superior posterior DMN--cuneus/pre-cuneus, inferior parietal lobule, cingulate

The key findings from the study include the following:

• Measures of hypoconnectivity in all three networks were identified in the psychotic bipolar and schizophrenia groups compared to controls.
• Unaffected psychotic bipolar disorder relatives had normal DMN measures in the three networks while the unaffected schizophrenic relatives showed hypoconnectivity in on one of the three networks.
• Genetic analysis revealed five genetic links to a brain connectivity sub-DMNs.
• Genes identified in this brain mapping linkage had previously been linked to psychosis and mood disorders

The five genetic clusters identified in this study were related to specific brain developmental and neuronal processes:

• NMDA long-term potentiation
• Protein kinase A regulation
• Immune response signaling
• Guidance of axonal development
• Synaptogenesis

The authors note an important advance in their study is the ability to

"dissect the underlying biological/molecular pathways and processes that might mediate genetic risk of psychosis via a valuable, noninvasive imaging marker."

Default mode network imaging and analysis is advancing as a promising research and clinical tool. It holds the promise of improving diagnostic accuracy and potentially improvement in targeting best treatment interventions for many brain disorders.

Readers with more interest in this topic can access the free full-text manuscript by clicking on the PMID link below.

Image of the cingulate fiber connectivity anatomy is an iPad screen shot from the app Brain Tutor.

Follow the author on Twitter WRY999

Meda SA, Ruaño G, Windemuth A, O'Neil K, Berwise C, Dunn SM, Boccaccio LE, Narayanan B, Kocherla M, Sprooten E, Keshavan MS, Tamminga CA, Sweeney JA, Clementz BA, Calhoun VD, & Pearlson GD (2014). Multivariate analysis reveals genetic associations of the resting default mode network in psychotic bipolar disorder and schizophrenia. Proceedings of the National Academy of Sciences of the United States of America, 111 (19) PMID: 24778245

Age-Specific Psychotic Effects with Cannabis Use

There is increasing evidence that some users of cannabis may be vulnerable to adverse cognitive effects including psychotic symptoms. Many adult casual users of cannabis appear to have minimal cognitive effects. However, younger users and those with underlying mood or psychotic disorders may experience significant adverse consequences of regular and heavy cannabis abuse. A previous post linking cannabis-related psychosis to family history of psychosis is posted here.

Schubart and colleagues in the Netherlands and UCLA recently analyzed the rates of reporting psychotic experiences in European (primarily Dutch-speaking)adolescents and young adults. They looked specifically for the rates of endorsement of psychotic and mood symptoms in adolescents grouped by frequency and quantity of cannabis use.
Psychotic symptom experience is commonly grouped into what are known as positive symptoms or negative symptoms. Positive symptoms of psychosis typically include delusions, auditory hallucinations and visual hallucinations. Negative symptoms of psychosis typically include loss of motivation, withdrawal, and lack of goal directed productivity.

Over 17,000 young adults participated in the survey with over two thirds of the respondents being classified as users. Looking at the entire group of regular cannabis users, their scores on measures of psychosis and depressive symptoms did not differ from those who reported not using cannabis.

However, two factors among the users identified subgroups with signficant endorsement of symptoms of psychopathology:

• Cannabis users who initiated use before the age of 12 were three times more likely than non-users to be in the top 10% of scores on psychotic positive symptoms
• Regular heavy cannabis users (greater than 25 euros spent per week on cannabis) were 2.8 to 3.4 times more likely to be in the top 10% of scorers on scales of positive and negative psychotic symptoms as well as depressive symptoms.

The authors noted in the discussion that this cross-sectional design can not prove a causal pathway. It is possible that young people with psychotic symptoms may be more likely to begin using cannabis. Additionally, they note that young age of onset of cannabis use may also indicate a larger cumulative exposure that could be related to psychotic and mood symptoms.

However, they do note their findings are consistent with the possibility that tetrahydrocannabinol (or other cannabis drugs)may have increased toxicity "during critical phases of brain maturation". There may be a window of vulnerability to the effcts of cannabis. Use after passing through this window, limited cannabis use may have limited cognitive effect. Early cannabis use and heavy chronic use may be a much different story. 

Photo of a black and yellow argiope spider from North Palm Beach Florida courtesy of Yates Photography.

Schubart CD, van Gastel WA, Breetvelt EJ, Beetz SL, Ophoff RA, Sommer IE, Kahn RS, & Boks MP (2010). Cannabis use at a young age is associated with psychotic experiences. Psychological medicine, 1-10 PMID: 20925969

Nicotine Replacement in Schizophrenia

Inpatient psychiatric hospitals increasingly prohibit smoking by patients, staff and family in their units.  Although the public health benefits of smoking restrictions are undeniable, there may be some situations where smoking restrictions have unintended consequences.  One area is the emergency management of patients with serious psychiatric illnesses such as schizophrenia and bipolar affective disorder.

Rates of smoking have been documented to be higher in both schizophrenia and bipolar affective disorder.  The likelihood is high that acute psychiatric emergencies in schizophrenia and bipolar will be accompanied by nicotine dependence.  Clinicians are left making a decision on how to manage nicotine dependence in the context of psychotic decompensation.

Michael Allen and colleagues recently conducted a small study of nicotine dependence management in forty subjects with schizophrenia admitted to a psychiatric emergency service.  Subjects were required to be smokers at the time of admission.  Severity of smoking dependence was assessed using the Fagerstrom scale.  Subjects received standard antipsychotic therapy without restriction but they were randomized to receive either nicotine replacement therapy (21 mg nicotine patch per day) or placebo patch.

Here is a summary of the results of the study:

• Nicotine replacement reduced a measure of agitation by 33% in the first four hours and 23% at 24 hours
• This reduction was statistically significantly more than with antipsychotic alone and placebo
• Subjects with lower nicotine dependence scores tended to show the most response compared to placebo
• The size of the effect of nicotine replacement on agitation reduction approached the level seen with standard antipsychotic therapy

So the beneficial effects of replacing nicotine in the short term in this population is pretty dramatic and of signifcant magnitude.  The authors note that it is possible the 21 mg nicotine patch is insufficient to address nicotine withdrawal in schizophrenics with more severe nicotine dependence.  Since the nicotine patch typically takes several hours to provide significant blood levels, the authors suggest a combination of nicotine gum (with rapid onset) and a patch may be the best strategy.

Encouraging patients with psychotic disorders and mood disorders to quit smoking is an important general health strategy.  However, this study suggests that attempting this during an acute psychotic break is probably counter productive and may be inhumane.  Acute nicotinie withdrawal may exacerbate the agitation of psychosis.  Nicotine withdrawal attempts in this population is probably better suited for periods where psychotic symptoms are under control.  It also makes sense to monitor patients with schizophrenia closely during attempts to stop smoking.  This period may be one of increased risk of psychiatric decompensation.

Photo of Nicotine Patch Courtesy of Wikipedia Creative Commons by RegBarc

Allen MH, Debanné M, Lazignac C, Adam E, Dickinson LM, & Damsa C (2011). Effect of nicotine replacement therapy on agitation in smokers with schizophrenia: a double-blind, randomized, placebo-controlled study. The American journal of psychiatry, 168 (4), 395-9 PMID: 21245085

Alzheimer's: Challenges in the Newly Diagnosed

Alois Alzheimer

Memory loss is a cardinal feature in the presentation and diagnosis of new patients with Alzheimer’s disease(AD).  However, the accompanying neurological and psychiatric problems seen in this population can be significant challenges.  Spalletta and colleagues have recently published a comprehensive assessment of the prevalence and types of problems families and clinicians face. 

Between 2003 and 2005, five Italian outpatient memory clinics studied a series of 1015 patients newly diagnosed with Alzheimer’s disease.  The subjects received a comprehensive assessment that including psychiatric, neurological and behavioral domains.  Men with newly diagnosed AD were contrasted with women newly diagnosed with AD to see if there were any specific gender effects in the findings.   Of interest, despite the new (recent) diagnosis, 40% of men and 47% of women already met criteria for severe dementia.  The authors note that there is significant variability in the timing of presentation for specialty evaluation and assessment.  Some find their way quickly, some only after dementia has progressed to a significant level.

The research team used a structured behavioral inventory called the Neuropsychiatric Inventory (NPI).  A factor analysis of the NPI showed 5 key factors that could be rated as absent, mild or clinically significant.  Here are the factors and prevalence rates in the sample for each of the domains men (women), (*-indicates statistical difference between men and women):

• Psychosis--8% (9%)
• Affective (Depression)--23% (32%)
• Mania- 2% (6%)*
• Psychomotor (agitation/irritability/aberrant motor behavior)—12% (11%)
• Apathy-37% (39%)
• At least one of the five syndromes—56% (61%)

The authors then examined how the prevalence for these neuropsychiatric problems correlated with the severity of dementia.  They found that severity increased four of the problem domains with most severe dementia raising risk from 70% for apathy to raising risk 420% for psychomotor problems.  Of note, depressive symptoms did not increase with severity of dementia. 

The authors note their study highlights the importance of assessing for apathy in this population.  The make it the most prevalent of the neuropsychiatric syndromes in the newly diagnosed with AD.   Apathy has been linked to neuropathological involvement in the medial frontal cortex and the anterior cingulate cortex in AD.

The authors note that their findings support looking for clusters of individual symptoms that make up these key five domains.  It would be helpful for future intervention studies (i.e. pharmacological/behavioral studies) to examine response over these domains.   We are seeing some recent clinical trials break out response of specific behavioral domains for drugs targeting AD.  A recent open label naturalistic study of the drug rivastigmine found apathy measures were more likely to improve than worsen over a 6 to 12 month follow up period.

Wikipedia Commons photo of Dr. Alois Alzheimer, Bavarian physician instrumental in describing the clinical features of dementia and discovering the histological brain changes characteristic of the illness.  Image estimated to be from about 1915 and is in the public domain due to expiration of any copyright.

Spalletta G, Musicco M, Padovani A, Rozzini L, Perri R, Fadda L, Canonico V, Trequattrini A, Pettenati C, Caltagirone C, & Palmer K (2010). Neuropsychiatric symptoms and syndromes in a large cohort of newly diagnosed, untreated patients with Alzheimer disease. The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry, 18 (11), 1026-35 PMID: 20808086


Gauthier S, Juby A, Dalziel W, Réhel B, Schecter R, & EXPLORE investigators (2010). Effects of rivastigmine on common symptomatology of Alzheimer's disease (EXPLORE). Current medical research and opinion, 26 (5), 1149-60 PMID: 20230208

Cannabis Use and Psychosis (Part 2)

I reviewed a research study last fall examining a Dutch study of cannabis use and psychotic symptoms.  That post is linked here.  In summary, the study suggested cannabis probably does not produce psychotic symptoms in the majority of users.  However, if you have a family member with a psychotic disorder (suggesting you may have a genetic risk for psychosis) you may be more likely to experience psychotic symptoms (i.e. hallucinations/delusions) with cannabis use.  This risk may be increased with higher potency cannabis formulations.

Now two additional research publications weigh in on this issue.  Both were published in the February 2011 issue of Archives of General Psychiatry.  Both studies come from the Genetic Risk and Outcome of Psychosis (GROUP) study sample.

The first manuscript summarized the results of study using a sibling-control and cross-sibling comparison.  Eleven hundred twenty subjects with a psychotic disorder were compared to 1057 siblings and 590 controls. In summary the results of this study were:

• You were much more likely to report psychotic symptoms (both positive and negative psychotic symptoms) with cannabis use if you had a sibling with psychosis
• Siblings using cannabis resembled psychotic siblings in their ratings much more than siblings not using cannabis
• The statistical analysis of the relationship pointed to a familial risk increasing cannabis sensitivity, rather than familial risk increasing use of cannabis

So this finding in in line with the original study.  Families may resemble each other in the way they respond to cannabis.  Some families may be particularly more likely to have psychotic symptoms in the context of cannabis use.

The second study takes another step to try to explain this relationship.  Can candidate genes be identified that are linked to this cannabis-linked psychosis effect?  If so, do these genes make biological sense or do they seem to just likely be random associations.

The answers proposed by the GROUP investigators are intriguing.  

• Sixteen single nucleotide proteins (SNPs) showed significant interactions
• The AKT1 gene status (C/C genotype) increased risk of psychosis after cannabis use
• AKT1 gene status explained 19% of the variance of psychotic symptoms in siblings with recent cannabis use
• The AKT1 gene is regulated by endogenous cannabanoid signaling
• This signal is downstream from the dopamine D2 receptor--a receptor known to be involving in psychosis and the target of antipsychotic drugs

The authors note that their proposed mechanism explains two commonly clinical findings:

• antipsychotic drugs do not block the psychotic effect of THC in those that experience psychosis with the drug
• substance abusing patients with schizophrenia respond more poorly to antipsychotic treatment

The explanation would be the endocannabanoid AKT1 effect is downstream from the D2 receptor.  Blocking the D2 receptor would have limited effects downstream from the receptor.

These two studies add to support for a role for cannabis to be a potential risk factor for some forms of psychosis and schizophrenia.  The genetic and molecular correlations in this study a mutually supportive.  So the take home message seems to be the same--there just seems to be more support the message is research based.  Some individuals may have a genetic risk for psychotic symptoms related to cannabis use.  This is not a trivial risk.  If you have a sibling or other relative with psychosis, or if you experience psychotic symptoms with cannabis use, don't use cannabis.

Photo of Back Yard Blue Jay in Tulsa after Snowfall Courtesy of Yates Photography

., Kahn, R., Linszen, D., van Os, J., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., & Myin-Germeys, I. (2010). Evidence That Familial Liability for Psychosis Is Expressed as Differential Sensitivity to Cannabis: An Analysis of Patient-Sibling and Sibling-Control Pairs Archives of General Psychiatry DOI: 10.1001/archgenpsychiatry.2010.132

van Winkel, R., , ., Kahn, R., Linszen, D., van Os, J., Wiersma, D., Bruggeman, R., Cahn, W., de Haan, L., Krabbendam, L., & Myin-Germeys, I. (2010). Family-Based Analysis of Genetic Variation Underlying Psychosis-Inducing Effects of Cannabis: Sibling Analysis and Proband Follow-up Archives of General Psychiatry, 68 (2), 148-157 DOI: 10.1001/archgenpsychiatry.2010.152