Microstructural white matter alterations associated to neurocognitive deficits in childhood leukemia survivors treated with cranial radiotherapy - a diffusional kurtosis study.

Background: Cranial radiotherapy (CRT) is a known risk factor for neurocognitive impairment in survivors of childhood acute lymphoblastic leukemia (ALL). Diffusion tensor imaging (DTI) and diffusional kurtosis imaging (DKI) are MRI techniques that quantify microstructural changes in brain white matter (WM) and DKI is regarded as the more sensitive of them. Our aim was to more thoroughly understand the nature of cognitive deficits after cranial radiotherapy (CRT) in adulthood after childhood ALL. Material and methods: Thirty-eight (21 women) ALL survivors, median age 38 (27-46) years, were investigated at median 34 years after diagnosis. All had been treated with a CRT dose of 24 Gy and with 11 years of complete hormone supplementation. DTI and DKI parameters were determined and neurocognitive tests were performed in ALL survivors and 29 matched controls. Results: ALL survivors scored lower than controls in neurocognitive tests of vocabulary, memory, learning capacity, spatial ability, executive functions, and attention (p < .001). The survivors had altered DTI parameters in the fornix, uncinate fasciculus, and ventral cingulum (all p < .05) and altered DKI parameters in the fornix, uncinate fasciculus, and dorsal and ventral cingulum (p < .05). Altered DTI parameters in the fornix were associated with impaired episodic verbal memory (r = -0.40, p < .04). The left and right uncinate fasciculus (r = 0.6, p < .001), (r = -0.5, p < .02) as well as the right ventral cingulum (r = 0.5, p < .007) were associated with impaired episodic visual memory. Altered DKI parameters in the fornix, right uncinate fasciculus (r = 0.3, r = 0.05, p = .02), and ventral cingulum (r = 0.3, p = .02) were associated with impaired results of episodic visual memory. Conclusion: ALL survivors with cognitive deficits demonstrated microstructural damage in several WM tracts that were more extensive with DKI as compared to DTI; this might be a marker of radiation and chemotherapy neurotoxicity underlying cognitive dysfunction.

Increase in hippocampal volume after electroconvulsive therapy in patients with depression: a volumetric magnetic resonance imaging study.

BACKGROUND: Major depression has traditionally been regarded as a neurochemical disease, but findings of a decreased hippocampal volume in patients with depression have turned the pathophysiological focus toward impairments in structural plasticity. The mechanisms of action of the most effective antidepressive treatment, electroconvulsive therapy (ECT), still remains elusive, but recent animal research has provided evidence for a cell proliferative effect in the hippocampus. The aim of this prospective study was to determine if hippocampal volume changes after ECT in patients with depression. METHODS: Twelve patients with depression and ongoing antidepressive pharmacological treatment were investigated with clinical ratings and 3 T magnetic resonance imaging within 1 week before and after the ECT series. Each hippocampus was manually outlined on coronal slices, and the volume was calculated. RESULTS: The left as well as the right hippocampal volume increased significantly after ECT. CONCLUSIONS: The hippocampal volume increases after ECT, supporting the hypothesis that hippocampus may play a central role in the treatment of depression.

Baseline verbal fluency performance as predictor of state anxiety during a live hand-grenade throwing exercise - A prospective study of Swedish military conscripts.

BACKGROUND: We investigated whether individual differences in baseline executive control capacity could predict state anxiety during a potentially life-threatening situation. METHODS: 19 Swedish military conscripts were assessed during two measurement occasions. During a baseline measurement, data regarding performance on a letter fluency task and state anxiety were assessed. During a second measurement, performed immediately prior to participation in a live hand-grenade throwing exercise, data regarding state anxiety was assessed. All participants were male, right-handed and had fulfilled 12 years of education. RESULTS: The level of state anxiety was significantly increased between the two measurement occasions (p < .01). Both the number of words produced (beta = -.37; p < .05) and the number of perseveration made (beta = .43; p < .05) on the verbal fluency task predicted, while controlling for state anxiety at baseline, the level of experienced state anxiety during the threatening situation. CONCLUSION: Although more research is needed the present finding suggests that individual differences in executive control capacity might be related to emotion regulation ability during acute stressor exposure.

A long-term longitudinal follow-up of depressed patients treated with ECT with special focus on development of dementia.

BACKGROUND: In this study, the long term effects of ECT on patients with depression were investigated through repeated rCBF and EEG measures as well as clinical characteristics over several years. The aim of the investigation was to establish an association with the eventual development of dementia. METHOD: A cohort of forty-nine patients (21 men and 28 women) with a mean age of 61 years underwent ECT. A subsequent evaluation from medical records and three rating-scales for diagnosis of Alzheimer´s disease (AD), fronto-temporal dementia (FTD), and for vascular dementia (VaD), revealed that 17 patients (8 men and 9 women), had developed dementia. These cases were compared to the 32 patients (13 men and 19 women), who had not developed dementia. RESULT: Initially, the dementia group, compared to those without dementia, showed a lower hemispheric CBF (left side; p=.029, right side; p=.033), and a lower mean occipital EEG frequency (p=.048). After the first ECT-series, an increase in general disorientation (p=.015), personal disorientation (p=.009), and subsequently, spatial disorientation (p=.021), were seen in the dementia group. There were no differences in the clinical response or remissions after treatment in the groups. LIMITATIONS: The small sample-size, which did not allow for the comparison of characteristics between different dementias. CONCLUSION: Depressed older patients who later developed dementia showed lower hemispheric mean level of CBF and EEG mean frequency before ECT and higher personal and spatial disorientation following ECT.

A long-term follow-up of clinical response and regional cerebral blood flow changes in depressed patients treated with ECT.

BACKGROUND: Depression is the leading cause of disability worldwide and electroconvulsive therapy (ECT) is the most potent therapy. We investigated the clinical response and regional cerebral blood flow changes in depressed in patients treated with (ECT) in a repeated longitudinal study. METHOD: Forty-nine patients (21 men and 28 women) with a mean age 61 years underwent ECT. Forty-one patients grading improvement after the initial ECT-series (responder group) were compared with eight, grading no improvement (non-responder group). The patients underwent neuropsychiatric ratings, measure of clinical response (defined as ≥50% reduction of pre-treatment depression score) and measure of regional cerebral blood flow (rCBF). RESULTS: The responder group had an initial 60-82%, and the non-responder group a 30-64% clinical response throughout the follow-up. The non-responder group showed more reported depression (p=.003), and vegetative anxiety (p=.024), with a generally higher left temporal rCBF (p=.045). LIMITATIONS: The retrospective approach and the small sample-size. CONCLUSION: Patients with no subjective improvement after ECT had lesser objective clinical response, more sustained reported depression with anxiety features, and higher left temporal rCBF.

Long-term cognitive sequelae after pediatric brain tumor related to medical risk factors, age, and sex.

BACKGROUND: Young age at diagnosis and treatment with cranial radiation therapy are well studied risk factors for cognitive impairment in pediatric brain tumor survivors. Other risk factors are hydrocephalus, surgery complications, and treatment with intrathecal chemotherapy. Female gender vulnerability to cognitive sequelae after cancer treatment has been evident in some studies, but no earlier studies have related this to tumor size. The purpose of our study was to find factors correlated with lowered IQ in a nationally representative sample of pediatric brain tumor patients referred for neuropsychologic evaluation. METHODS: Sixty-nine pediatric brain tumor patients, diagnosed 1988-2005 and tested 1995-2006, were included in the study. In a series of stepwise multiple regressions, the relationship of IQ to disease, treatment, and individual variables (sex and syndromes) were evaluated. A subanalysis was made of the covariation between sex and tumor size. RESULTS: The patients had generally suppressed IQ and impairments in executive function, memory, and attention. Lowered IQ was associated with young age at diagnosis, being male, tumor size, and treatment with whole-brain radiation therapy. A sex difference was evident for patients with increased intracranial pressure at diagnosis with males having larger tumors. Tumor size was found to be a better predictor of cognitive sequelae than sex. CONCLUSIONS: Whole-brain radiation therapy, large tumors, young age at diagnosis, and male gender are risk factors for late cognitive sequelae after pediatric brain tumors. When examining sex differences, tumor size at diagnosis needs to be taken into account.

Access to neuropsychologic services after pediatric brain tumor.

BACKGROUND: Increasing survival rates for children with brain tumors creates a greater need for neuropsychologic follow-up and intervention. The aim of this study was to evaluate rates of referral by medical doctors to neuropsychologic services and patient and treatment factors that differentiated referred and nonreferred patients. METHODS: Data were retrieved from medical records of all pediatric brain tumor patients in southern Sweden diagnosed between 1993 and 2004 who survived more than 1 year (n = 132). Characteristics of the patients, the cancer, and treatment received were then compared for patients who were and were not referred for neuropsychologic examination during that period. RESULTS: Sixty-four (48%) of the pediatric brain tumor patients were referred for neuropsychologic evaluation. These patients had significantly larger tumors, more recurrences of cancer, and increased intracranial pressure at diagnosis when compared with the nonreferred group (n = 68). However, most of the patients in the nonreferred group either had significant risk factors for cognitive impairment or were reporting impairments that would suggest a referral was warranted. CONCLUSIONS: Given the high rates of cognitive impairment in children with brain tumors, referral to neuropsychologic services should be considered in all survivors. In addition to improving long-term adjustment, systematic referral can provide data on cognitive impairments, making it possible to evaluate different cancer treatment protocols not only in terms of survival but also in terms of quality of survival. Greater efforts are needed to disseminate and raise awareness about published guidelines on the long-term care of pediatric brain tumor patients.

Glial cell activation in response to electroconvulsive seizures.

Electroconvulsive therapy (ECT) is a very efficient treatment for severe depression. However, cognitive side effects have raised concern to whether ECT can cause cellular damage in vulnerable brain regions. A few recent animal studies have reported limited hippocampal cell loss, while a number of other studies have failed to find any signs of cellular damage and some even report that electroconvulsive seizures (ECS; the animal counterpart of ECT) has neuroprotective effects. We previously have described gliogenesis in response to ECS. Loss of glial cells is seen in depression and de novo formation of glial cells may thus have an important therapeutic role. Glial cell proliferation and activation is however also seen in response to neuronal damage. The aim of the present study was to further characterize glial cell activation in response to ECS. Two groups of rats were treated with 10 ECS using different sets of stimulus parameters. ECS-induced changes in the morphology and expression of markers typical for reactive microglia, astrocytes and NG2+ glial cells were analyzed immunohistochemically in prefrontal cortex, hippocampus, amygdala, hypothalamus, piriform cortex and entorhinal cortex. We observed changes in glial cell morphology and an enhanced expression of activation markers 2 h following ECS treatment, regardless of the stimulus parameters used. Four weeks later, few activated glial cells persisted. In conclusion, ECS treatment induced transient glial cell activation in several brain areas. Whether similar processes play a role in the therapeutic effect of clinically administered ECT or contribute to its side effects will require further investigations.

Life-time adversities, reported thirteen years after a suicide attempt: relationship to recovery, 5HTTLPR genotype, and past and present morbidity.

In this study, we investigated how adversities related to past and present morbidity, and genotype. Forty-two, suicide attempters and 22 matched control patients were followed-up after 13 years. Life-time adversities were explored in an interview, and the patients were reassessed psychiatrically. The serotonin-transporter-linked promotor region (5-HTTLPR) was typed. More adversities were reported by suicide attempters than controls, and by still-ill than recovered suicide attempters. Adversities reported at follow-up were related to psychiatric morbidity at follow-up, but not to morbidity 13 years earlier. The 5-HTTLPR, genotype was associated with reported adversities, but not chances of recovery. Adversities potentially affected chronic morbidity. 5-HTTLPR genotype did not affect long-term recovery.

The interaction between baseline trait anxiety and trauma exposure as predictor of post-trauma symptoms of anxiety and insomnia.

In this study a prospective design was used to investigate the interaction between baseline trait anxiety and exposure to traumatic situations on post-trauma symptoms of anxiety and insomnia in a sample of Swedish peacekeeping soldiers serving in Kosovo. The result showed that pre-trauma trait anxiety interacted with exposure to traumatic situations predicting a higher post-trauma distress. Further, baseline trait anxiety and baseline symptoms of anxiety and insomnia predicted post-trauma symptoms of anxiety and insomnia. The results support a diathesis stress model in which high trait anxiety interacts with trauma exposure in the elicitation of anxiety-related distress but the study needs to be replicated before further conclusions can be drawn.

Changes in frontal lobe activity with cognitive therapy for spider phobia.

Patients suffering from spider phobia were studied with measurement of regional cerebral blood flow (rCBF) when they were looking at a video recording of living spiders. Six patients were studied before and after cognitive psychotherapy with successful outcome in all cases. On each occasion rCBF was measured under 3 conditions: during rest, during exposure to a video recording of neutral nature scenery, and finally while the patient watched a recording of living spiders. The patients who managed to control their emotional reactions without panicking during spider exposure before treatment showed an rCBF increase in prefrontal cortex, more pronounced in the right hemisphere. Following successful treatment, these patients showed an rCBF decrease in this region. In contrast, patients who reported panic during the initial spider exposure showed hypoactivity in the frontal cortex at that time, and then showed an increase in prefrontal rCBF in the spider challenge after cognitive therapy. The psychological improvement from cognitive therapy thus appears to be associated with activation of prefrontal cortex that varies closely with the demands for self-regulation of emotional reactivity.

Long-term follow-up in depressed patients treated with electroconvulsive therapy.

DESIGN: Our aim was to study the long-term effects of electroconvulsive therapy (ECT) in depression. A total of 55 patients were followed-up 20 to 24 years after an ECT series; 13 patients were still alive, and 10 agreed to participate in the study. All 55 patients had been investigated with clinical and neuropsychological assessment and with neurophysiological measurements and with regional cerebral blood flow (rCBF) and EEG before the first ECT, 6 months later, and after approximately 1 year. These investigations were repeated in the 10 patients. RESULTS: Before the original ECT series, all patients had suffered from severe mood disorder. At follow-up, the 10 patients showed no clear signs of mood disorder or cognitive impairment. There was a slightly subnormal performance in working memory and in verbal as well as visual episodic memory on all 3 occasions after the ECT series. The rCBF measurement showed a significant average CBF decrease from the first to the last measurement. There was, moreover, a significant rCBF decrease in frontal areas at the last measurement compared with the 3 previous assessments. CONCLUSION: All ten patients followed-up 20 to 24 years after an ECT series were mentally healthy and thus besides a moderate visual memory dysfunction, no severe side effects were observed with clinical and neuroimaging techniques.