Facilitatory Effect of Intermittent Repetitive Transcranial Magnetic Stimulation on Perceptual Distortion of the Face.

Orofacial pain patients often report that the painful facial area is "swollen" without clinical signs - known as perceptual distortion (PD). The neuromodulatory effect of facilitatory repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals was investigated, to provide further support that the primary somatosensory cortex (SI) is involved in facial PD. Participants were allocated to active (n = 26) or sham (n = 26) rTMS group in this case-control study. PD was induced experimentally by injecting local anesthesia (LA) in the right infraorbital region. PD was measured at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. Intermittent theta-burst stimulation (iTBS) as active rTMS and sham rTMS was applied to the face representation area of SI at 10 min after LA. The magnitude of PD was compared between the groups. The magnitude of PD significantly increased immediately after iTBS compared with sham rTMS (P = .009). The PD was significantly higher immediately after iTBS compared to 6 min after LA (P = .004) in the active rTMS group, but not in the sham rTMS group (P = .054). iTBS applied to a somatotopic-relevant cortical region appears to facilitate facial PD further supporting the involvement of SI in the processing of one´s own face and PD. PERSPECTIVE: This study provides information on neural substrate responsible for processing of perceptual distortion of the face which is speculated to contribute to the chronification of orofacial pain. The findings of this study may aid in mechanism-based management of the condition in orofacial pain disorders and possibly other chronic pain states.

Low-frequency rTMS inhibits the anti-depressive effect of ECT. A pilot study.

OBJECTIVE: Low-frequency repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex has been shown to have a statistically and clinically significant anti-depressant effect. The present pilot study was carried out to investigate if right prefrontal low-frequency rTMS as an add-on to electroconvulsive therapy (ECT) accelerates the anti-depressant effect and reduces cognitive side effects. METHODS: In this randomised, controlled, double-blind study, thirty-five patients with major depression were allocated to ECT+placebo or ECT+low-frequency right prefrontal rTMS. The severity of depression was evaluated during the course using the Hamilton scale for depression (the 17-item as well as the 6-item scale) and the major depression inventory (MDI). Furthermore, neuropsychological assessment of cognitive function was carried out. RESULTS: The study revealed no significant difference between the two groups for any of the outcomes, but with a visible trend to lower scores for MDI after treatment in the placebo group. The negative impact of ECT on neurocognitive functions was short-lived, and scores on logical memory were significantly improved compared to baseline 4 weeks after last treatment. The ECT-rTMS group revealed generally less impairment of cognitive functions than the ECT-placebo group. CONCLUSION: The addition of low-frequency rTMS as an add-on to ECT treatment did not result in an accelerated response. On the contrary, the results suggest that low-frequency rTMS could inhibit the anti-depressant effect of ECT.

Effect of repetitive transcranial magnetic stimulation on altered perception of One's own face.

BACKGROUND: Chronic orofacial pain (COP) patients often perceive the painful face area as "swollen" without clinical signs; such self-reported illusions of the face are termed perceptual distortion (PD). The pathophysiological mechanisms underlying PD remain elusive. OBJECTIVE: To test the neuromodulatory effect of repetitive transcranial magnetic stimulation (rTMS) on PD in healthy individuals, to gain insight into the cortical mechanisms underlying PD. METHODS: PD was induced experimentally by injections of local anesthetic (LA) around the infraorbital nerve and measured as perceived size changes of the affected area. Participants were randomly allocated to inhibitory rTMS (n = 26) or sham rTMS (n = 26) group. The participants rated PD at baseline, 6 min after LA, immediately, 20 and 40 min after rTMS. The rTMS (inhibitory and sham) was applied to face (lip) representation area of primary somatosensory cortex (SI) as an intervention at 10 min after the LA, when the magnitude of PD is large. As inhibitory rTMS, continuous theta-burst stimulation paradigm (50 Hz) for 40s was employed to inhibit cortical activity. RESULTS: We demonstrated a significant decrease in the magnitude of PD immediately and 20 min after the application of inhibitory rTMS compared with sham rTMS (P < 0.006). In two control experiments, we also showed that peripheral muscle stimulation and stimulation of a cortical region other than the lip representation area had no effect on the magnitude of the PD. CONCLUSIONS: Inhibitory rTMS applied to a somatotopical-relevant cortical region modulates PD of the face in healthy individuals and could potentially have therapeutic implications for COP patients.

[Post-concussion syndrome is a neuro-cognitive condition].

Post-concussion syndrome (PCS) is often caused by an uncomplicated mild head injury but followed by long-lasting somatic, cognitive and psychiatric symptoms. For many years PCS has been an area of controversy between clinicians. New diagnostic techniques and clinical researches has shed light to some neurobiological aspects behind PCS. In Diagnostic and Statistical Manual of Mental Disorders V PCS is redefined as a neuro-cognitive condition emphasizing the importance of neuropsychological deficits among these patients. New clinical recommendations do not support previous concept of long-term rest, but suggest gradual training back to a daily life.

[Repetitive transcranial magnetic stimulation treatment for post-traumatic stress disorder].

Approximately 10% of combat soldiers and 30% of rape victims develop post-traumatic stress disorder (PTSD). Repetitive transcranial magnetic stimulation (rTMS) is already known to be safe in depression treatment. Research results of the past 15 years indicate that rTMS induced to the right dorsolateral prefrontal cortex may have a potential to treat the symptoms of PTSD. Furthermore, high-frequency rTMS seems to be superior to low-frequency rTMS. The effect of rTMS on PTSD symptoms could be mediated by increasing the level of brain-derived neurotrophic factor.

Capillary dysfunction: its detection and causative role in dementias and stroke.

In acute ischemic stroke, critical hypoperfusion is a frequent cause of hypoxic tissue injury: As cerebral blood flow (CBF) falls below the ischemic threshold of 20 mL/100 mL/min, neurological symptoms develop and hypoxic tissue injury evolves within minutes or hours unless the oxygen supply is restored. But is ischemia the only hemodynamic source of hypoxic tissue injury? Reanalyses of the equations we traditionally use to describe the relation between CBF and tissue oxygenation suggest that capillary flow patterns are crucial for the efficient extraction of oxygen: without close capillary flow control, "functional shunts" tend to form and some of the blood's oxygen content in effect becomes inaccessible to tissue. This phenomenon raises several questions: Are there in fact two hemodynamic causes of tissue hypoxia: Limited blood supply (ischemia) and limited oxygen extraction due to capillary dysfunction? If so, how do we distinguish the two, experimentally and in patients? Do flow-metabolism coupling mechanisms adjust CBF to optimize tissue oxygenation when capillary dysfunction impairs oxygen extraction downstream? Cardiovascular risk factors such as age, hypertension, diabetes, hypercholesterolemia, and smoking increase the risk of both stroke and dementia. The capillary dysfunction phenomenon therefore forces us to consider whether changes in capillary morphology or blood rheology may play a role in the etiology of some stroke subtypes and in Alzheimer's disease. Here, we discuss whether certain disease characteristics suggest capillary dysfunction rather than primary flow-limiting vascular pathology and how capillary dysfunction may be imaged and managed.

Brain energy metabolism and blood flow differences in healthy aging.

Cerebral metabolic rate of oxygen consumption (CMRO(2)), cerebral blood flow (CBF), and oxygen extraction fraction (OEF) are important indices of healthy aging of the brain. Although a frequent topic of study, changes of CBF and CMRO(2) during normal aging are still controversial, as some authors find decreases of both CBF and CMRO(2) but increased OEF, while others find no change, and yet other find divergent changes. In this reanalysis of previously published results from positron emission tomography of healthy volunteers, we determined CMRO(2) and CBF in 66 healthy volunteers aged 21 to 81 years. The magnitudes of CMRO(2) and CBF declined in large parts of the cerebral cortex, including association areas, but the primary motor and sensory areas were relatively spared. We found significant increases of OEF in frontal and parietal cortices, excluding primary motor and somatosensory regions, and in the temporal cortex. Because of the inverse relation between OEF and capillary oxygen tension, increased OEF can compromise oxygen delivery to neurons, with possible perturbation of energy turnover. The results establish a possible mechanism of progression from healthy to unhealthy brain aging, as the regions most affected by age are the areas that are most vulnerable to neurodegeneration.

Assessing response to stroke thrombolysis: validation of 24-hour multimodal magnetic resonance imaging.

BACKGROUND: Imaging is used as a surrogate for clinical outcome in early-phase stroke trials. Assessment of infarct growth earlier than the standard 90 days used for clinical end points may be equally accurate and more practical. OBJECTIVE: To compare assessment of the effect of reperfusion therapies using 24-hour vs day 90 magnetic resonance imaging. DESIGN: Infarct volume was assessed on diffusion-weighted imaging (DWI) at baseline and 24 hours after stroke onset and on fluid-attenuated inversion recovery images at day 90. The DWI and fluid-attenuated inversion recovery lesions were manually outlined by 2 independent raters, and the volumes were averaged. Interrater consistency was assessed using the median difference in lesion volume between raters. SETTING: Referral center. Patients  Imaging data were available for 83 patients; 77 of these patients received thrombolysis. MAIN OUTCOME MEASURES: Infarct volume at 24 hours and 90 days. RESULTS: The 24-hour DWI infarct volume had a strong linear correlation with day 90 fluid-attenuated inversion recovery infarct volume (r = 0.98, 95% confidence interval, 0.97-0.99). Recanalization had a significant effect on infarct evolution between baseline and 24 hours but not between 24 hours and day 90. Infarct growth from baseline was significantly reduced by recanalization, whether assessed at 24 hours or day 90. Infarct volume at either time point predicted functional outcome independent of age and baseline stroke severity. Interrater agreement was better for DWI than fluid-attenuated inversion recovery (1.4 mL [8%] vs 1.8 mL [17%]; P = .002). CONCLUSIONS: Assessment of final infarct volume using DWI at 24 hours captures the effect of reperfusion therapies on infarct growth and predicts functional outcome similarly to imaging at day 90. This has the potential to reduce loss to follow-up in trials and may add early prognostic information in clinical practice.

Variable ATP yields and uncoupling of oxygen consumption in human brain.

The distribution of brain oxidative metabolism values among healthy humans is astoundingly wide for a measure that reflects normal brain function and is known to change very little with most changes of brain function. It is possible that the part of the oxygen consumption rate that is coupled to ATP turnover is the same in all healthy human brains, with different degrees of uncoupling explaining the variability of total oxygen consumption among people. To test the hypothesis that about 75% of the average total oxygen consumption of human brains is common to all individuals, we determined the variability in a large group of normal healthy adults. To establish the degree of variability in different regions of the brain, we measured the regional cerebral metabolic rate for oxygen in 50 healthy volunteers aged 21-66 and projected the values to a common age of 25.Within each subject and region, we normalized the metabolic rate to the population average of that region. Coefficients of variation ranged from 10 to 15% in the different regions of the human brain and the normalized regional metabolic rates ranged from 70% to 140% of the population average for each region, equal to a two-fold variation. Thus the hypothetical threshold of oxygen metabolism coupled to ATP turnover in all subjects is no more than 70% of the average oxygen consumption of that population.

[The effect of vitamin D on neuropsychiatric conditions]. / D-vitamins betydning for neuropsykiatriske tilstande.

Vitamin D receptors have recently been identified in immune cells as well as various parts of the brain. Vitamin D deficiency seems to be involved in the patho-immunological process of multiple sclerosis. Hypovitaminosis D has also been associated with different psychiatric conditions, including depression and schizophrenia. Results from more than 250 publications concluded that patients with both schizophrenia and bipolar condition are more frequently born in winter and spring, the periods which have the largest maternal decline in plasma concentrations of vitamin D.

Carbogen inhalation increases oxygen transport to hypoperfused brain tissue in patients with occlusive carotid artery disease: increased oxygen transport to hypoperfused brain.

Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the vasoconstrictive effect of oxygen on cerebral arterioles. Based on a recent study in normal volunteers, we now claim that the vasodilatory effect of carbon dioxide predominates when 5% CO(2) is added to inhaled oxygen (the mixture known as carbogen). In the present study, we measured CBF by positron emission tomography (PET) during inhalation of test gases (O(2), carbogen, and atmospheric air) in healthy volunteers (n = 10) and in patients with occlusive carotid artery disease (n = 6). Statistical comparisons by an additive ANOVA model showed that carbogen significantly increased CBF by 7.51 + or - 1.62 ml/100 g/min while oxygen tended to reduce it by -3.22 + or - 1.62 ml/100 g/min. A separate analysis of the hemisphere contralateral to the hypoperfused hemisphere showed that carbogen significantly increased CBF by 8.90 + or - 2.81 ml/100 g/min whereas oxygen inhalation produced no reliable change in CBF (-1.15 + or - 2.81 ml/100 g/min). In both patients and controls, carbogen was as efficient as oxygen in increasing Sa(O2) or PaO(2) values. The study demonstrates that concomitant increases of CBF and Sa(O2) are readily obtained with carbogen, while oxygen increases only Sa(O2). Thus, carbogen improves oxygen transport to brain tissue more efficiently than oxygen alone. Further studies with more subjects are, however, needed to investigate the applicability of carbogen for long-term inhalation and to assess its therapeutic benefits in acute stroke patients.

[11C]Mirtazapine binding in depressed antidepressant nonresponders studied by PET neuroimaging.

RATIONALE: Lack of benefit from antidepressant drug therapy is a major source of human suffering, affecting at least 25% of people with major depressive disorder. We want to know whether nonresponse to antidepressants can be linked to aberrant neuroreceptor binding. OBJECTIVE: This study aims to assess the antidepressant binding in brain regions of depressed nonresponders compared with healthy controls. MATERIALS AND METHODS: Healthy volunteers and depressed subjects who had failed to benefit from at least 2 antidepressant treatments were recruited by newspaper advertisements. All subjects had received no antidepressant medication for at least 2 months before positron emission tomography (PET) that was carried out with [11C]mirtazapine. Kinetic parameters of [11C]mirtazapine were determined from PET data in selected brain regions by the simplified reference tissue model. RESULTS: Binding potentials of [11C]mirtazapine in cerebral cortical regions were lower in depressed nonresponders than in healthy controls. Removal rates of [11C]mirtazapine were higher in diencephalic regions of depressed nonresponders than in healthy controls. CONCLUSIONS: PET neuroimaging with [11C]mirtazapine showed aberrant neuroreceptor binding in brain regions of depressed subjects who had failed to benefit from treatment with antidepressant drugs.

Safety and efficacy of MRI-based selection for recombinant tissue plasminogen activator treatment: responder analysis of outcome in the 3-hour time window.

INTRODUCTION: The use of MRI may alter the target population for intravenous recombinant tissue plasminogen activator (rtPA) treatment relative to conventional CT. If selection changes, it remains crucial to demonstrate safety and efficacy of rtPA for the overall population, as well as in subpopulations hypothesized to benefit from MRI. MATERIALS AND METHODS: Clinical outcome and incidence of symptomatic intracerebral hemorrhage (ICH) was recorded in 112 consecutive patients treated with intravenous rtPA (0-3 h) with MRI as first-choice imaging modality. According to the responder analysis, favorable outcome was separately defined for mild (NIHSS <8; n = 51), moderate (NIHSS 8-14; n = 30) and severe (NIHSS >14; n = 31) stroke. RESULTS: Eighty-three patients were treated with rtPA after MRI, and 29 after CT. Adjusted for baseline severity, 42% of all patients had a favorable outcome, compared to 37% in NINDS. Among patients with severe stroke, MR-selected patients showed a good outcome in 52% of patients compared to 29% in NINDS (p < 0.05). Symptomatic ICH occurred in 2 patients (1.9 %), and 7 patients died during hospitalization (6.3%). CONCLUSION: MRI-based rtPA is safe and time-efficient. Outcome data compares well with NINDS data. Diagnostic information obtained from multimodal MRI may affect the target group. Our data support the hypothesized benefit of MRI in patients with severe stroke.

Neuroimaging of mirtazapine enantiomers in humans.

INTRODUCTION: Mirtazapine is a racemic antidepressant with a multireceptor profile. Previous studies have shown that the enantiomers of mirtazapine have different pharmacologic effects in the brain of laboratory animals. MATERIALS AND METHODS: In the present study, we used positron emission tomography (PET) and autoradiography to study effects of (R)- and (S)-[(11)C]mirtazapine in the human brain. Detailed brain imaging by PET using three methods of kinetic data analysis showed no reliable differences between regional binding potentials of (R)- and (S)-[(11)C]mirtazapine in healthy subjects. RESULTS: Autoradiographic studies carried out in whole hemispheres of human brain tissue showed, however, that (R)- and (S)-mirtazapine differ markedly as inhibitors of [(3)H]clonidine binding at alpha(2)-adrenoceptors. CONCLUSION: The multireceptor binding profiles of mirtazapine enantiomers, along with individual differences between subjects, may preclude PET neuroimaging from demonstrating reliable differences between the regional distribution and binding of (R)- and (S)-[(11)C]mirtazapine in the living human brain.

Normalization in PET group comparison studies--the importance of a valid reference region.

INTRODUCTION: In positron emission tomography (PET) studies of cerebral blood flow (CBF) and metabolism, the large interindividual variation commonly is minimized by normalization to the global mean prior to statistical analysis. This approach requires that no between-group or between-state differences exist in the normalization region. Given the variability typical of global CBF and the practical limit on sample size, small group differences in global mean easily elude detection, but still bias the comparison, with profound consequences for the physiological interpretation of the results. MATERIALS AND METHODS: Quantitative [15O]H2O PET recordings of CBF were obtained in 45 healthy subjects (21-81 years) and 14 patients with hepatic encephalopathy (HE). With volume-of-interest (VOI) and voxel-based statistics, we conducted regression analyses of CBF as function of age in the healthy group, and compared the HE group to a subset of the controls. We compared absolute CBF values, and CBF normalized to the gray matter (GM) and white matter (WM) means. In additional simulation experiments, we manipulated the cortical values of 12 healthy subjects and compared these to unaltered control data. RESULTS: In healthy aging, CBF was shown to be unchanged in WM and central regions. In contrast, with normalization to the GM mean, CBF displayed positive correlation with age in the central regions. Very similar artifactual increases were seen in the HE comparison and also in the simulation experiment. CONCLUSION: Ratio normalization to the global mean readily elevates CBF in unchanged regions when a systematic between-group difference exists in gCBF, also when this difference is below the detection threshold. We suggest that the routine normalization to the global mean in earlier studies resulted in spurious interpretations of perturbed CBF. Normalization to central WM yields less biased results in aging and HE and could potentially serve as a normalization reference region in other disorders as well.

MRI detection of early blood-brain barrier disruption: parenchymal enhancement predicts focal hemorrhagic transformation after thrombolysis.

BACKGROUND AND PURPOSE: Blood-brain barrier disruption may be a predictor of hemorrhagic transformation (HT) in ischemic stroke. We hypothesize that parenchymal enhancement (PE) on postcontrast T1-weighted MRI predicts and localizes subsequent HT. METHODS: In a prospective study, 33 tPA-treated stroke patients were imaged by perfusion-weighted imaging, T1 and FLAIR before thrombolytic therapy and after 2 and 24 hours. RESULTS: Postcontrast T1 PE was found in 5 of 32 patients (16%) 2 hours post-thrombolysis. All 5 patients subsequently showed HT compared to 11 of 26 patients without PE (P=0.043, specificity 100%, sensitivity 31%), with exact anatomic colocation of PE and HT. Enhancement of cerebrospinal fluid on FLAIR was found in 4 other patients, 1 of which developed HT. Local reperfusion was found in 4 of 5 patients with PE, whereas reperfusion was found in all cases of cerebrospinal fluid hyperintensity. CONCLUSIONS: PE detected 2 hours after thrombolytic therapy predicts HT with high specificity. Contrast-enhanced MRI may provide a tool for studying HT and targeting future therapies to reduce risk of hemorrhagic complications.

[Imaging of the pathophysiology in acute stroke]. / Billeddiagnostik af patofysiologien ved akut apopleksi.

Recent developments in neuroimaging have changed the diagnostic aspect of acute stroke and improved our understanding of stroke pathophysiology. Both diffusion weighted MR imaging and CT are capable of detecting the infarcted volume damaged by cytotoxic edema. However, within six hours of stroke onset, DWI has both higher sensitivity and specificity than CT. Perfusion weighted MR imaging and perfusion CT can identify the tissue at risk surrounding the core of the infarct. CT and MR-angiography contribute important information concerning the intra and extracerebral arteries.

[Thrombolysis of apoplexy patients. A year's experience and results in Aarhus Hospital]. / Trombolyse af apopleksipatienter. Første års erfaringer og resultater på Arhus Sygehus.

INTRODUCTION: Treatment of acute stroke with thrombolysis within three hours is a challenging aspect of the organization of state-of-the-art stroke care. Indication for thrombolysis is based on studies where CT was used as a diagnostic tool. MR-based techniques are in some aspects superior to CT, though the scan times are longer. In this study, the feasibility and effectiveness of MR-based thrombolysis was examined. MATERIALS AND METHODS: Prospective registration of patient time delays, demographics, initial NIHSS (National Institute of Health Stroke Scale) and MR data for all patients referred to Aarhus Hospital with symptoms of acute stroke was done over a one-year period. For patients receiving thrombolysis, additional MR data, complications, NIHSS at follow-up (2 hours, 24 hours, 7 days and 3 months) and modified Rankin score at 3 months were recorded. Results were compared to the data in the international thrombolysis database (SITS-MOST). RESULTS: During the period, 112 patients were referred and 86 were scanned using MR techniques. 22 patients received thrombolysis (17/5 after MR/CT). 54% of patients had a good outcome at 3 months (mRS = 0-1) compared to 34% in SITS-MOST (n.s). No symptomatic haemorrhages were recorded; mortality was 9% (13% in SITS-MOST). Treatment was not delayed compared to SITS-MOST despite the longer MR scan time. CONCLUSION: Effective organization of treatment with thrombolysis using MR imaging is feasible. The MR techniques were beneficial in decision making and did not cause delay of treatment. Thrombolysis in this setup was as efficient with respect to outcome and complications as was that recorded in the SITS-MOST register.

Ischemic injury detected by diffusion imaging 11 minutes after stroke.

A 78-year-old woman suffered a stroke inside a magnetic resonance scanner while being imaged because of a brief transient ischemic attack 2 hours earlier. Diffusion-weighted images obtained 11 minutes after stroke showed tissue injury not found on initial images. The data show early, abrupt diffusion changes in hypoperfused tissue, adding to our understanding of the progression of microstructural abnormalities in the hyperacute phase of stroke.