Peter Zimmermann

Plasticity of Hippocampal Subfield Volume Cornu Ammonis 2+3 Over the Course of Withdrawal in Patients With Alcohol Dependence

IMPORTANCEnResearch focusing on plasticity has shown adult neurogenesis in hippocampal subfields. Chronic alcoholism is associated with decreased plasticity and reduced whole hippocampal volume that could contribute to neuropsychiatric characteristics and outcome of the disease.nnnOBJECTIVEnTo investigate the effect of alcohol abstinence on neuronal plasticity measured as longitudinal volume change in distinct hippocampal subfields.nnnDESIGN, SETTING, AND PARTICIPANTSnWe acquired high-resolution structural images of 42 patients addicted to alcohol and 32 healthy control participants. Patients and control participants were both scanned twice, once after withdrawal and 2 weeks later.nnnMAIN OUTCOMES AND MEASURESnVolumes of hippocampal subfields cornu ammonis (CA) 2+3, CA4+dentate gyrus, and subiculum were determined with a user-independent segmentation method.nnnRESULTSnWe found plasticity effects in bilateral CA2+3 in patients addicted to alcohol. Compared with healthy control participants, patients had lower CA2+3 volume at pretest (t31u2009=u2009-0.73, Pu2009=u2009.47) and showed a significant normalization of gray matter volume 2 weeks later. Pretest CA2+3 (t31u2009=u2009-3.93, Pu2009<u2009.001) volume was negatively associated with years of regular alcohol consumption (r42u2009=u2009-0.32, Pu2009<u2009.05) and more severe alcohol-withdrawal symptoms (r38u2009=u2009-0.35, Pu2009<u2009.05). Patients with stronger withdrawal symptoms displayed the largest volume increase of CA2+3 (r38u2009=u20090.55, Pu2009<u2009.001).nnnCONCLUSIONS AND RELEVANCEnThe observed normalization of the bilateral hippocampal CA2+3 volume deficit matches animal data, showing a strong increase of hippocampal neurogenesis after cessation of alcohol consumption, and fits the reported increase of patients cognitive function within a few months of alcohol abstinence. The role of CA3 in pattern separation and completion is also critical for formation of hallucinations, which constitute a severe symptom of the withdrawal syndrome. The study adds further biological arguments from structural brain research to abstain from alcohol.

Military deployment correlates with smaller prefrontal gray matter volume and psychological symptoms in a subclinical population

Research investigating the effects of trauma exposure on brain structure and function in adults has mainly focused on post-traumatic stress disorder (PTSD), whereas trauma-exposed individuals without a clinical diagnoses often serve as controls. However, this assumes a dichotomy between clinical and subclinical populations that may not be supported at the neural level. In the current study we investigate whether the effects of repeated or long-term stress exposure on brain structure in a subclinical sample are similar to previous PTSD neuroimaging findings. We assessed 27 combat trauma-exposed individuals by means of whole-brain voxel-based morphometry on 3u2009T magnetic resonance imaging scans and identified a negative association between duration of military deployment and gray matter volumes in ventromedial prefrontal cortex (vmPFC) and dorsal anterior cingulate cortex (ACC). We also found a negative relationship between deployment-related gray matter volumes and psychological symptoms, but not between military deployment and psychological symptoms. To our knowledge, this is the first whole-brain analysis showing that longer military deployment is associated with smaller regional brain volumes in combat-exposed individuals without PTSD. Notably, the observed gray matter associations resemble those previously identified in PTSD populations, and concern regions involved in emotional regulation and fear extinction. These findings question the current dichotomy between clinical and subclinical populations in PTSD neuroimaging research. Instead, neural correlates of both stress exposure and PTSD symptomatology may be more meaningfully investigated at a continuous level.

Complex Real Life-Related Prospective Memory in Soldiers with and Without Post-Traumatic Stress Disorder

Objective: Posttraumatic stress disorder (PTSD) is known toxa0influence memory functions in a complex fashion. However, littlexa0is known about the impact of PTSD on future directed mnemonicxa0functions like prospective memory (PM).xa0 nMethods: The present study aimed at examining performance of 13xa0soldiers with PTSD, 12 without PTSD and 21 non-military controlsxa0without PTSD across different phases of a real life-related PMxa0paradigm. In addition, neuropsychological tests of memory and thexa0influence of salivary cortisol levels on memory performance wereassessed.Results: Soldiers with PTSD performed significantly worse duringxa0the planning and retrieval phase of time- and event-dependent PMxa0compared to the non-military controls, but not to soldiers withoutxa0PTSD. Moreover, PTSD symptom severity correlated negativelyxa0with PM retrieval. In soldiers without PTSD time- and eventdependentxa0PM was significantly declined during retrieval phasexa0compared to the non-military controls. Significantly decreasedxa0salivary cortisol levels were detected only for soldiers with PTSD.xa0Standard neuropsychological assessment showed significantlyxa0impaired working- and retrospective long-term memory in bothsoldiers with and without PTSD.Conclusion: Our results indicate for the first time that exposurexa0to combat-related stress may have selective deteriorating effectsxa0on real-life-related PM and other memory functions in the absencexa0of a PTSD diagnosis. We conclude that stress-related alterationsxa0of memory functions in soldiers may not only be related toPTSD-related changes in cortisol metabolism. Rather, additionalxa0neuropeptides and/or neurohormones may be involved in thexa0emergence of memory dysfunctions resulting from combat-relatedxa0stress.

Risk factors for mental health aeromedical evacuation among German armed forces soldiers deployed to Afghanistan

Due to deployment-related stress, a considerable number of soldiers have to be evacuated from theater. Medical reports of all soldiers who were evacuated for mental health reasons during the 22nd German ISAF Contingent (u200aN = 35) were evaluated with regard to sociodemographic and operational factors. Data were compared with a questionnaire survey of the same contingent (u200aN = 1,165). Logistic regression showed a significantly higher risk of evacuation for soldiers who had participated in combat (Exp. B: 7.9; p = .002), those who had been stationed in Kunduz (Exp. B: 4.1; p = .005), and soldiers under the age of 26 (Exp. B: 4.0; p = .013).These pilot study data can help identify target groups for more comprehensive measures of stress prevention.

Serum concentrations of TNF-α, sTNF-R p55 and p75 and post-traumatic stress in German soldiers

Growing evidence suggests involvement of the tumor necrosis factor (TNF)-α system in the pathophysiology of psychiatric disorders. Research into post-traumatic stress disorder (PTSD) has investigated serum levels of TNF-α, but not to date its soluble receptors sTNF-R p55 and sTNF-R p75. We examined serum levels of TNF-α, sTNF-R p55 and sTNF-R p75 in 135 male German soldiers 70 of whom had been deployed abroad and 65 in Germany only. Post-traumatic stress symptoms were measured using the Post-traumatic Stress Diagnostic Scale (PDS) and the Trier Inventory for the Assessment of Chronic Stress (TICS). Correlational analysis controlling for multiple testing, showed no significant Spearman rank correlations between PDS or TICS scores and serum levels of TNF-α, sTNF-R p55 or sTNF-R p75, either in the full sample or in the group of soldiers who had been deployed abroad. ANCOVAs showed no significant differences between soldiers with or without a PDS-derived diagnosis of PTSD, or between soldiers with or without deployment abroad, after controlling for age, smoking and body mass index (BMI). These results suggest that the TNF-α system, as reflected by TNF-α, sTNF-R p55 and sTNF-R p75 serum levels, does not play a major role in the pathophysiology and development of PTSD symptoms as measured by the PDS and the TICS. However, several methodological and contextual issues have to be considered.

Neural correlates of response bias: Larger hippocampal volume correlates with symptom aggravation in combat-related posttraumatic stress disorder

The diagnosis of posttraumatic stress disorder (PTSD) is vulnerable to the simulation or exaggeration of symptoms as it depends on the individuals self-report of symptoms. The use of symptom validity tests is recommended to detect malingering in PTSD. However, in neuroimaging research, PTSD diagnosis is often taken at face validity. To date, no neuroimaging study has compared credible PTSD patients with those identified as malingering, and the potential impacts of including malingerers along with credible patients on results is unclear. We classified male patients with combat-related PTSD as either credible (nxa0=xa037) or malingerers (nxa0=xa09) based on the Morel Emotional Numbing Test and compared structural neuroimaging and psychological questionnaire data. Patients identified as malingerers had larger gray matter volumes in the hippocampus, right inferior frontal gyrus and thalamus, and reported higher PTSD symptoms than credible PTSD patients. This is the first structural neuroimaging study to compare credible PTSD patients and malingerers. We find evidence of structural differences between these groups, in regions implicated in PTSD, inhibition and deception. These results emphasize the need for the inclusion of SVTs in neuroimaging studies of PTSD to ensure future findings are not confounded by an unknown mix of valid PTSD patients and malingerers.

Cognitive Reappraisal and Expressive Suppression of Negative Emotion in Combat-Related Posttraumatic Stress Disorder: A Functional MRI Study

Difficulties in the regulation of emotion are hypothesized to play a key role in the development and maintenance of posttraumatic stress disorder (PTSD). The current study used functional magnetic resonance imaging (fMRI) to assess neural activity during task preparation and image presentation during different emotion regulation strategies, cognitive reappraisal and expressive suppression, in PTSD. Patients with combat-related PTSD (nu2009=u200918) and combat-exposed controls (nu2009=u200927) were instructed to feel, reappraise or suppress their emotional response prior to viewing combat-related images during fMRI, while also providing arousal ratings. In the reappraise condition, patients showed lower medial prefrontal neural activity during task preparation and higher prefrontal neural activity during image presentation, compared with controls. No difference in neural activity was observed between the groups during the feel or suppress conditions, although patients rated images as more arousing than controls across all three conditions. By distinguishing between preparation and active regulation, and between reappraisal and suppression, the current findings reveal greater complexity regarding the dynamics of emotion regulation in PTSD and have implications for our understanding of the etiology and treatment of PTSD.

Serum concentrations of TNF-α and its soluble receptors during psychotherapy in German soldiers suffering from combat-related PTSD

BACKGROUNDnChanges in serum concentrations of tumor necrosis factor-α (TNF-α) and its soluble receptors (sTNF-R) p55 and p75 have been shown to be associated with various psychiatric treatments.nnnSUBJECTS AND METHODSnBefore and after treatment, serum levels of TNF-α, sTNF-R p55 and sTNF-R p75 were measured in 38 German soldiers who had been deployed abroad and suffered from combat-related post-traumatic stress disorder (PTSD). Patients were randomized either to inpatient psychotherapy (N=21) including eye movement desensitization and reprocessing (EMDR) or to outpatient clinical management (N=17). Symptoms of PTSD were measured using the Post-traumatic Stress Diagnostic Scale (PDS).nnnRESULTSnThe PDS score significantly decreased across time in both groups. Serum concentrations of TNF-α increased, while sTNF-R p55 and sTNF-R p75 levels decreased significantly. After the treatment period, we could not detect any significant difference regarding TNF-α, sTNF-R p55 or sTNF-R p75 levels between the inpatient psychotherapy group and the outpatient clinical management control group.nnnCONCLUSIONSnThis relatively small clinical study suggests that specific inpatient psychotherapy but also non-specific supportive outpatient treatment for PTSD are associated with changes in the TNF-α system. This may represent an immunological effects or side effects of psychotherapy.To the Editor: With great interest we read the original article of Chen et al.[1] published in the Chinese Medical Journal comparing serum concentrations of cytokines in patients of Han and Li ethnicity with posttraumatic stress disorder (PTSD). The authors found significantly higher serum concentrations of the cytokines interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-α in PTSD patients compared to normal controls, and differences in cytokine concentrations according to ethnicity. n nAt the Bundeswehr (German Armed Forces) Hospital in Berlin, Germany, we recently performed a study including 135 male German soldiers of which seventy had been deployed abroad. In the subsample of soldiers deployed abroad, 38 suffered from combat-related PTSD according to the Tenth Revision of the International Classification of Diseases criteria after their deployment, whereas 32 soldiers did not. All seventy subjects were of German ethnicity. TNF-α and its soluble receptors TNF-R p55 and p75 were measured in the serum using an individually arranged Bio-Plex Pro™ human cytokine immunoassay from Bio-Rad, Germany. n nTo compare our study results with those of Chen et al.,[1] we analyzed data of N = 70 soldiers deployed abroad. One-way analysis of variance revealed no statistically significant differences for TNF-α and TNF-R p75 levels between groups (with or without PTSD). Only TNF-R p55 serum concentrations differed significantly (F [1, 66] = 10.76, P = 0.002). For a boxplot of TNF-R p55 levels [Figure 1]. In a consecutive analysis of covariance controlling for age and body mass index (BMI), the difference in TNF-R p55 levels was no longer statistically significant (F [1, 55] <1, nonsignificant). Age (F [1, 55] = 5.23, P = 0.026) and BMI (F [1, 55] = 9.15, P = 0.004) explained 23.4% of variance. n n n nFigure 1 n nBoxplot of TNF-R p55 levels of soldiers with (n = 38) and without (n = 32) posttraumatic stress disorder. Although one-way analysis of variance revealed a significant difference of TNF-R p55 serum concentrations between both groups (F [1, 66] = 10.76, ... n n n nTherefore, our results obtained from a sample of male German soldiers could not replicate the finding of Chen et al.[1] of elevated TNF-α levels in Chinese civilian patients with PTSD. One has to keep in mind that the studies differ on race, ethnicity, sex, occupation, and geographical context of participants. However, there are comparable studies,[2,3] which also report elevated TNF-α levels in PTSD patients similar to Chen et al.[1] n nAge and BMI seem to be important variables influencing TNF-R p55 levels.[4] In our sample of German soldiers, this influence of age and BMI on TNF-R p55 levels was greater than the influence of PTSD. The dependence of TNF-R p55 levels, as well as TNF-α and TNF-R p75 levels on age and BMI, has been reported several times before, for example, in a general population sample.[4] n nIn summary, considering the cited articles[1,4] and our own study together, we conclude that ethnicity, age, and BMI appear to be important variables influencing the levels of TNF-α and its soluble receptors. Therefore, these parameters should be taken into account when investigating serum concentrations of TNF-α and its receptors in the studies of PTSD and other conditions. n nFinancial support and sponsorship nThis work was financially supported by the Claussen-Simon-Foundation. n n nConflicts of interest nThere are no conflicts of interest.

Serum Concentrations of Tumor Necrosis Factor-α and its Soluble Receptors in Soldiers with and Without Combat-related Posttraumatic Stress Disorder: Influence of Age and Body Mass Index

BACKGROUNDnChanges in serum concentrations of tumor necrosis factor-α (TNF-α) and its soluble receptors (sTNF-R) p55 and p75 have been shown to be associated with various psychiatric treatments.nnnSUBJECTS AND METHODSnBefore and after treatment, serum levels of TNF-α, sTNF-R p55 and sTNF-R p75 were measured in 38 German soldiers who had been deployed abroad and suffered from combat-related post-traumatic stress disorder (PTSD). Patients were randomized either to inpatient psychotherapy (N=21) including eye movement desensitization and reprocessing (EMDR) or to outpatient clinical management (N=17). Symptoms of PTSD were measured using the Post-traumatic Stress Diagnostic Scale (PDS).nnnRESULTSnThe PDS score significantly decreased across time in both groups. Serum concentrations of TNF-α increased, while sTNF-R p55 and sTNF-R p75 levels decreased significantly. After the treatment period, we could not detect any significant difference regarding TNF-α, sTNF-R p55 or sTNF-R p75 levels between the inpatient psychotherapy group and the outpatient clinical management control group.nnnCONCLUSIONSnThis relatively small clinical study suggests that specific inpatient psychotherapy but also non-specific supportive outpatient treatment for PTSD are associated with changes in the TNF-α system. This may represent an immunological effects or side effects of psychotherapy.To the Editor: With great interest we read the original article of Chen et al.[1] published in the Chinese Medical Journal comparing serum concentrations of cytokines in patients of Han and Li ethnicity with posttraumatic stress disorder (PTSD). The authors found significantly higher serum concentrations of the cytokines interleukin (IL)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-α in PTSD patients compared to normal controls, and differences in cytokine concentrations according to ethnicity. n nAt the Bundeswehr (German Armed Forces) Hospital in Berlin, Germany, we recently performed a study including 135 male German soldiers of which seventy had been deployed abroad. In the subsample of soldiers deployed abroad, 38 suffered from combat-related PTSD according to the Tenth Revision of the International Classification of Diseases criteria after their deployment, whereas 32 soldiers did not. All seventy subjects were of German ethnicity. TNF-α and its soluble receptors TNF-R p55 and p75 were measured in the serum using an individually arranged Bio-Plex Pro™ human cytokine immunoassay from Bio-Rad, Germany. n nTo compare our study results with those of Chen et al.,[1] we analyzed data of N = 70 soldiers deployed abroad. One-way analysis of variance revealed no statistically significant differences for TNF-α and TNF-R p75 levels between groups (with or without PTSD). Only TNF-R p55 serum concentrations differed significantly (F [1, 66] = 10.76, P = 0.002). For a boxplot of TNF-R p55 levels [Figure 1]. In a consecutive analysis of covariance controlling for age and body mass index (BMI), the difference in TNF-R p55 levels was no longer statistically significant (F [1, 55] <1, nonsignificant). Age (F [1, 55] = 5.23, P = 0.026) and BMI (F [1, 55] = 9.15, P = 0.004) explained 23.4% of variance. n n n nFigure 1 n nBoxplot of TNF-R p55 levels of soldiers with (n = 38) and without (n = 32) posttraumatic stress disorder. Although one-way analysis of variance revealed a significant difference of TNF-R p55 serum concentrations between both groups (F [1, 66] = 10.76, ... n n n nTherefore, our results obtained from a sample of male German soldiers could not replicate the finding of Chen et al.[1] of elevated TNF-α levels in Chinese civilian patients with PTSD. One has to keep in mind that the studies differ on race, ethnicity, sex, occupation, and geographical context of participants. However, there are comparable studies,[2,3] which also report elevated TNF-α levels in PTSD patients similar to Chen et al.[1] n nAge and BMI seem to be important variables influencing TNF-R p55 levels.[4] In our sample of German soldiers, this influence of age and BMI on TNF-R p55 levels was greater than the influence of PTSD. The dependence of TNF-R p55 levels, as well as TNF-α and TNF-R p75 levels on age and BMI, has been reported several times before, for example, in a general population sample.[4] n nIn summary, considering the cited articles[1,4] and our own study together, we conclude that ethnicity, age, and BMI appear to be important variables influencing the levels of TNF-α and its soluble receptors. Therefore, these parameters should be taken into account when investigating serum concentrations of TNF-α and its receptors in the studies of PTSD and other conditions. n nFinancial support and sponsorship nThis work was financially supported by the Claussen-Simon-Foundation. n n nConflicts of interest nThere are no conflicts of interest.