It’s really a slow digestion per...

It’s really a slow digestion period, getting back from SfN in Atlanta. Other than an aching back and jet-lag the conference experience has been tremendous. But at the same time it was rather confusing. Those talks and lectures that I expected to be good turned out to be boring or far too complex (or ill presented) to comprehend. Other talks — IMO wildcards relative to my own area — were tremendously informative.

It strikes me that this year didn’t have one or more major themes that were dominating the discussion and themes as such. This very much as we’ve seen in previous conferences, and at other conferences, where topics such as e.g. stem cell research (SfN) or brain development or imaging genetics (Human Brain Mapping) was on everybody’s lips. So while I sit here back home and reflect on some highlights — other than those very technical aspects that I myself found interesting — a few come to mind.

It strikes me that the reporter at Nature found the following topic particularly interesting: the effects of verbal child abuse on brain structure and function. Basically, what researchers find is a number of brain pathologies and/or changes in brains of people who have been exposed to verbl abuse during childhood.

Exposure to childhood verbal abuse is associated with abnormalities in auditory cortex and hippocampus

*M. H. TEICHER1, A. TOMODA1, K. LIBESNEY1, A. POLCARI1, C. P. NAVALTA1, N. SODATO2;
1Dept Psychiatry, Harvard Med Sch, Belmont, MA, 2Cerebral Research, National Institute for Physiological Sciences, Okazaki, Aichi, JAPAN.

We have recently reported that early exposure to parental verbal abuse (VA) is associated with psychiatric symptomatology in early adulthood that is comparable to the effects of exposure to non-familial sexual abuse and witnessing of domestic violence (Teicher et al 2006). In the current study we examined the association between exposure to VA and measures of brain morphometry.
The sample consisted of 17 healthy unmedicated right-handed subjects (6M/11F [18-22 years of age]) with high-level exposure to VA, but without exposure to any other form of trauma, and 17 carefully-matched healthy controls. Volumetric brain images were acquired with a 3T Siemens Trio scanner and processed using optimized voxel-based morphometry (VBM) for regional differences in grey matter volume (GMV).
There were significant reductions in GMV of right (-9.9%) and left (-9.2%) superior temporal gyri (STG) of abused subjects. Degree of exposure correlated with GMV of left STG for the entire sample (r=-0.38, p=0.02). Measures of verbal memory correlated with degree of GMV reduction in left STG (r=-0.39). Males were more strongly affected, and also had a 15.9% and 13.8% reduction in left and right superior frontal gyrus.
A major consequence of exposure to VA was limbic irritability, characterized by symptoms of dissociation, sensory disturbances, and automatisms. Ratings of limbic system irritiability on the limbic system checklist correlated strongly with GMV deficits in left (p < 0.0001) and right (p < 0.0001) hippocampus. Subjects exposed to high levels of VA also had a 13-point reduction in verbal IQ.
This study suggests that exposure to parental VA may significantly impact brain development targeting superior temporal gyrus and auditory cortex, which are known to be plastic structure. Further, there is evidence for correlative abnormalities in hippocampus, which may help to explain their heightened degree of vulnerability to psychiatric symptomatology.

The other top story was the neural correlates of suicide, and the debate whether suicide is a psychiatric abberation in its own right. Here are some SfN abstracts on suicide:

Corticotropin-releasing hormone receptor-1 in the prefrontal cortex and hippocampus of teenage suicide victims

*X. REN1, Y. DWIVEDI1, R. C. ROBERTS2, R. R. CONLEY2, G. N. PANDEY1;
1Dept Psychiat, Univ Illinois Chicago, Chicago, IL, 2Psychiatry, Maryland Psychiatric Research Center, Baltimore, MD.

Suicide is a major public health concern, and in youths, it is the second most frequent cause of death in the United States. Although the neurobiology of adult suicide has been studied, the neurobiology of teenage suicide has been relatively unexplored. Recent studies suggest that there is a disturbance in the hypothalamic-pituitary-adrenal axis in psychiatric patients, including suicide victims. In order to determine if there is an abnormality in corticotropin-releasing hormone receptor-1 (CRH-R1)-mediated signaling system in teenage suicide victims, we measured the CRH-R1 protein level in the prefrontal cortex (PFC) and hippocampus (HIPPO) of teenage suicide victims and normal control subjects by using Western blot. We found that there was a significant decrease in the CRH-R1 protein levels in the PFC (N = 16, mean ± SD: 66 ± 28, p<0.01), but not in the HIPPO (N = 18, mean ± SD: 102 ± 33) of teenage suicide victims compared with matched normal control subjects (PFC, N = 16, mean ± SD: 100 ± 30; HIPPO, N = 18, mean ± SD: 100 ± 35). We then compared the CRH-R1 protein levels in PFC of teenage suicide victims with or without a history of psychiatric illness and found no significant difference in these two subgroups. The results indicate that the change of CRH-R1 protein levels in the PFC may be related to the pathophysiology of teenage suicide.

The role of the serotonin 2C receptor mRNA editing in suicidal behavior

*S. DRACHEVA1,2, N. PATEL2, D. A. WOO2, L. J. SIEVER1,2, J. SCHMEIDLER2, V. HAROUTUNIAN1,2;
1Dept. Psychiat, Bronx VA Med Ctr, Bronx, NY, 2Psychiatry, Mount Sinai School of Medicine, New York, NY.

The 5-HT2C receptor (5-HT2CR) in brain is present in numerous isoforms that are created by post-transcriptional modification of its mRNA, termed “RNA editing”. This editing can modify one or more of five adenosine residues (named A, B, E, C, D) to inosine giving rise to up to 24 functionally distinct 5-HT2CR isoforms that vary in their agonist-induced and constitutive activity.
To date, three different studies (Niswender et al., 2001; Gurevich et al., 2002; Iwamoto and Kato, 2003) have detected changes in the editing efficiencies of the 5-HT2CR in the prefrontal cortex (PFC) of suicide victims. However, methodological constraints and/or limited sample size have led to inconsistent results precluding reliable distinctions between changes associated specifically with suicidal behavior vs. underlying psychiatric disorders. The present study compared the editing efficiencies of 5-HT2CR in the PFC of 22 subjects who died from suicide to those of 83 subjects who did not. The entire study cohort consisted of 35 subjects with bipolar disorder (BP), 35 subjects with schizophrenia (SZ), and 35 matched normal controls (NC). Fifteen and 7 of the 22 suicide victims were diagnosed with BP or SZ, respectively. The RNA samples were provided by the Stanley Foundation. The editing analysis was performed by sequencing ~ 45 individual clones from each subject.
Repeated measures ANOVA compared 5 editing sites in subjects with three different diagnoses (DXs) (BP, SZ, NC) who did or did not commit suicide. There were significant main effects of site (p<<0.001) and suicide (p=0.003), but not for DX or for any interactions. Excluding NCs, who did not have any suicides, did not change the results substantially. Separate ANOVAs for each editing site indicated significant suicide differences for all sites except E. Separate ANOVAs for six major protein isoforms indicated a significant suicide difference for one of them (VSV) (p<0.0005), which is the most expressed isoform in the human PFC and constitutes ~25% of all 5-HT2CR proteins.
These data indicate significant over-expression of the 5-HT2CR isoform that activates G-protein coupling least efficiently in the PFC of suicide victims compared to non-suicide subjects. This effect is not influenced by the underling psychiatric conditions of the suicide subjects.

A quantitative immunocytochemical study of the human anterior cingulate cortex in normal and suicide subjects

*Y. LIU1, E. K. FUNG1, A. J. DWORK2, V. ARANGO3;
1Neuroscience, New York State Psychitric Inst, New York, NY, 2Psychiatry, Pathology and Neuronscience, Columbia University and New York State Psychitric Inst, New York, NY, 3Psychiatry and Neuroscience, Columbia University and New York State Psychitric Inst, New York, NY.

The cingulate cortex is implicated in emotion, attention, mood states, motor functions and cognitive processes. We found alterations in serotonin transporter and 5-HT1A receptors postmortem and in vivo in this brain region in depression and suicide. Within the cingulate gyrus, the anterior cingulate cortex (ACC, Broadmann area 24b) is a proisocortical agranular cortex which projects to both the orbital prefrontal cortex and the basolateral nucleus of the amygdala, and is uniquely positioned to contribute to aberrant emotion processing in psychopathology. Recent postmortem studies suggest that glutamic acid decarboxylase (GAD) dysregulation occurs in the ACC in schizophrenia and bipolar disorder. We examined the ACC of eleven normal controls (Male/Female=10/1) and six suicides (Male/Female=2/4). Neurons were stained with an antibody against neuronal nuclei (NeuN), while hematoxylin staining was used to identify glial cell nuclei. Adjacent sections were immunostained with GAD65/67 antibody. Neuronal and glial density was determined using the optical disector. The majority of the GAD-immunoreactive (IR) neurons are small (867±263 µm3) compared to other neurons (1875±681 µm3) and have typical bipolar or multipolar interneuron morphology. In the ACC of controls, we observed that the density of GAD-IR neurons (GD) was 43% of the total neuronal density (ND). The ratio of glial cell density to neuronal density is 1.4:1. In suicides there was a similar GD/ND ratio (39%) and we did not find significant differences in the cell densities of NeuN or GAD-IR neurons in suicides compared to controls. In this small preliminary study neuronal volume did not differ in suicides (1770±228 µm3) and controls 1932±840 µm3). Under microscopic examination, the density of GAD-IR terminals in the suicides is similar to that of the controls. However, the absence of alterations in cell density does not necessarily imply an absence of alterations in the total cell number. Furthermore, functional differences in disease may result from changes in subtypes of interneurons, rather than from their total number. Further studies are necessary to determine whether the GAD dysregulation found in the ACC in schizophrenia is also present in suicide.

-Thomas