Cerebral blood flow and transcranial doppler sonography measurements of CO2-reactivity in acute traumatic brain injured patients.

BACKGROUND: Cerebral blood flow (CBF) measurements are helpful in managing patients with traumatic brain injury (TBI), and testing the cerebrovascular reactivity to CO(2) provides information about injury severity and outcome. The complexity and potential hazard of performing CBF measurements limits routine clinical use. An alternative approach is to measure the CBF velocity using bedside, non-invasive, and transcranial Doppler (TCD) sonography. This study was performed to investigate if TCD is a useful alternative to CBF in patients with severe TBI. METHOD: CBF and TCD flow velocity measurements and cerebrovascular reactivity to hypocapnia were simultaneously evaluated in 27 patients with acute TBI. Measurements were performed preoperatively during controlled normocapnia and hypocapnia in patients scheduled for hematoma evacuation under general anesthesia. MAIN FINDING AND CONCLUSION: Although the lack of statistical correlation between the calculated reactivity indices, there was a significant decrease in TCD-mean flow velocity and a decrease in CBF with hypocapnia. CBF and TCD do not seem to be directly interchangeable in determining CO(2)-reactivity in TBI, despite both methods demonstrating deviation in the same direction during hypocapnia. TCD and CBF measurements both provide useful information on cerebrovascular events which, although not interchangeable, may complement each other in clinical scenarios.

CSF biomarkers correlate with cerebral blood flow on SPECT in healthy elderly.

BACKGROUND: The preclinical patterns of biological markers for Alzheimer's disease (AD) in vivo need further exploration. The aim of this study was therefore to investigate CSF biomarkers, regional cerebral blood flow (rCBF) and cognitive performance in cognitively healthy older individuals. METHOD: Within a 2-week period, 32 cognitively healthy older individuals underwent CSF analysis, rCBF measurement and cognitive testing. The CSF was analysed for ß-amyloid(1-42) (Aß42), total tau protein (T-tau) and hyperphosphorylated tau protein (P-tau). The rCBF results were analysed with statistical parametric mapping to investigate rCBF covariance with the other measurements. RESULTS: High CSF P-tau and T-tau levels correlated with decreased rCBF in the right superior posterior medial frontal lobe whereas high CSF P-tau levels also correlated with increased rCBF in the left fronto-temporal border zone area. No significant covariance was seen between rCBF and CSF Aß42. Neither CSF P-tau and T-tau levels nor rCBF in the current right frontal and left posterior locations were associated with cognitive performance. CONCLUSIONS: Our findings suggest a possible correlation between tau pathology and blood flow abnormalities in individuals without any overt cognitive symptoms. An association with AD development is possible but other explanatory mechanisms cannot be excluded.

Size of basal ganglia in suicide attempters, and its association with temperament and serotonin transporter density.

Magnetic resonance imaging was used to compare subcortical volumes of seven suicide attempters with those of six healthy controls. Suicide attempters had 10% smaller right caudate nucleus and 19% bilaterally smaller globus pallidus. In suicide attempters, volumes of the globus pallidus correlated negatively with previously reported measures of solidity (non-impulsive temperament) and serotonin transporter binding potential.

Prediction of recidivism in a long-term follow-up of forensic psychiatric patients: Incremental effects of neuroimaging data.

One of the primary objectives in forensic psychiatry, distinguishing it from other psychiatric disciplines, is risk management. Assessments of the risk of criminal recidivism are performed on a routine basis, as a baseline for risk management for populations involved in the criminal justice system. However, the risk assessment tools available to clinical practice are limited in their ability to predict recidivism. Recently, the prospect of incorporating neuroimaging data to improve the prediction of criminal behavior has received increased attention. In this study we investigated the feasibility of including neuroimaging data in the prediction of recidivism by studying whether the inclusion of resting-state regional cerebral blood flow measurements leads to an incremental increase in predictive performance over traditional risk factors. A subsample (N = 44) from a cohort of forensic psychiatric patients who underwent single-photon emission computed tomography neuroimaging and clinical psychiatric assessment during their court-ordered forensic psychiatric investigation were included in a long-term (ten year average time at risk) follow-up. A Baseline model with eight empirically established risk factors, and an Extended model which also included resting-state regional cerebral blood flow measurements from eight brain regions were estimated using random forest classification and compared using several predictive performance metrics. Including neuroimaging data in the Extended model increased the area under the receiver operating characteristic curve (AUC) from .69 to .81, increased accuracy from .64 to .82 and increased the scaled Brier score from .08 to .25, supporting the feasibility of including neuroimaging data in the prediction of recidivism in forensic psychiatric patients. Although our results hint at potential benefits in the domain of risk assessment, several limitations and ethical challenges are discussed. Further studies with larger, carefully characterized clinical samples utilizing higher-resolution neuroimaging techniques are warranted.

Serotonin transporter gene polymorphisms: effect on serotonin transporter availability in the brain of suicide attempters.

The efficacy of serotonin reuptake inhibitors in depression and anxiety disorders suggests the gene coding for the serotonin transporter (5-HTT), SLC6A4, as a candidate of importance for these conditions. Positive findings regarding associations between polymorphisms in SLC6A4 have been reported, indicating that these polymorphisms may influence anxiety-related personality traits, as well as the risk of developing depression and suicidality. Serotonin 5-HTT availability was assessed with single photon emission computed tomography (SPECT), using (123)I-beta-CIT as ligand, in a population of unmedicated male suicide attempters (n=9) and in matched controls (n=9). Two polymorphisms in SLC6A4 were assessed, including the 5-HTTLPR located in the promoter region and a variable number of tandem repeats (VNTR) polymorphism in intron 2 (STin2). In suicide attempters, but not in controls, low 5-HTT availability was associated with the S allele of 5-HTTLPR and with the 12 repeat allele of STin2. Data suggest that polymorphisms in SLC6A4 may influence the expression of the brain serotonin transporter in suicide attempters.

Human cerebral blood volume (CBV) measured by dynamic susceptibility contrast MRI and 99mTc-RBC SPECT.

BACKGROUND: Patients with elevated intracranial pressure risk compromising their cerebral blood flow, resulting in ischemia. Lowering of the raised intracranial pressure, is therefore, mandatory. Reduction of the cerebral blood volume (CBV) might be target. In finding ways to do so, one has to be able to measure CBV. Measurement of CBV is, however, difficult. Radio(99mTc-)labeled erythrocytes (99mTcRBC) single photon emission computer-aided tomography (SPECT) is one established method used for CBV measurement. Recently, dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI), has also been successfully used for this purpose. The aim of this study was to validate the use of DSC-MRI for the measurement of CBV by the investigation of the correlation between the regional distributions of 99mTc-RBC SPECT and DSC-MRI measurement of CBV in humans. If possible, the aim was also to find a conversion constant that will enable the DCS-MRI to be interpreted as CBV (percent of brain volume). METHODS: CBV of 8 volunteers were studied under normocapnic and hypocapnic conditions. CBV was measured with both 99mTc-RBC SPECT and DSC-MRI. RESULTS: There were significant correlations between the regional distributions of CBV measured by 99mTc-RBC SPECT and DSC-MRI (rest: F=4.53, P<0.05; hypocapnia: F=9.61, P<0.005). The derived conversion factor between DSC-MRI voxel values and 99mTc-RBC SPECT CBV (percent of brain volume) at rest was 0.0059+/-0.0013. Global CBV during normocapnia was 4.3%+/-0.6% of brain volume as measured by SPECT of brain volume and 4.5%+/-0.9% as measured by MRI. Decreasing the end-tidal pCO2 by 1.8 kPa by spontaneous hyperventilation reduced the global CBV significantly to 3.9%+/-0.5% in the SPECT group and to 3.5%+/-0.6% in the MRI group. CONCLUSIONS: The comparison of 99mTc-RBC SPECT and DSC-MRI measurements in our study indicates that DSC-MRI can be a useful method to measure CBV as a percent of brain volume.

Improved lumbar infusion test analysis for normal pressure hydrocephalus diagnosis.

OBJECTIVES: Constant infusion lumbar infusion test (LIT) is an important way to find which patients, of those with signs and symptoms corresponding to normal pressure hydrocephalus (NPH) who will improve from shunt operation. LIT is a stress test on the ability for cerebrospinal fluid re-absorbtion. The aim of this study is to show how the information from LIT can be improved by quantitative analysis and avoidance of methodological pitfalls. MATERIAL AND METHODS: The potential pitfalls, and the analysis method, are described in detail. The analysis was applied on pre-operative constant infusion LIT from 31 patients operated for NPH, with known outcome. The pre- and post-operative walking speed was used to grade pathology progression or improvement. RESULTS: The maximal, plateau, intra-spinal pressure at constant infusion LIT is an ambivalent indicator for NPH: while low maximal pressure indicates no cerebrospinal fluid (CSF) absorbtion pathology, too high pressure (≥47 mmHg) may mean no diagnosis, because of stenosis of the Sylvian aqueduct. When subjects with too high intra-spinal pressure were excluded, the new analysis gave a couple of diagnostic volume parameters, of which one appears to be an optimal LIT parameter for identifying NPH patients with 14% better accuracy than plateau pressure. CONCLUSION: By avoiding methodological pitfalls, and optimal analysis of the results from lumbar infusion test, the number of NPH patients who do not have a successful outcome after shunt operation may be further decreased.

Regional brain serotonin and dopamine transporter binding capacity in suicide attempters relate to impulsiveness and mental energy.

To study different aspects of regional pre-synaptic brain (123)I-beta-CIT uptake on serotonin and dopamine re-uptake sites in drug-free suicide attempters in comparison with age- and sex matched control subjects, single photon emission computed tomography (SPECT) measurements were analysed for regional serotonin re-uptake (5HTT) and dopamine re-uptake (DAT) capacity (binding potential, BP()) after i.v. (123)I-beta-CIT administration. All suicide attempters were examined concerning seriousness of the attempt, and DSM-IV diagnosis. Both suicide attempters and control subjects were tested for psychotropic drugs, and completed the Marke-Nyman Temperament (MNT) test, including solidity (level of impulsiveness/initiative) and validity (level of mental energy). We found no significant difference between suicide attempters and control subjects concerning the regional levels of 5HTT BP() or DAT BP(). However, in suicide attempters, but not controls, we found significant regional correlations between MNT variables and SPECT results. We interpret the discrepant findings in suicide attempters and control subjects to be due to a disability of the suicide attempters to regulate their serotonin and dopamine levels, e.g. in response to external stress.

SPECT findings in children with specific language impairment.

Findings from 99mTc-HMPAO SPECT measurements at rest in a group of 19 school-age children with specific language impairment (SLI) were compared to a group of 12 children with attention-deficit hyperactivity disorder (ADHD). The regional cerebral blood flow (CBF) distributions were different in the two groups. Children with SLI showed significantly lower CBF values in the right parietal region and in the subcortical region compared to the ADHD group. In addition, the SLI group had symmetric CBF distributions in the left and right temporal regions, whereas the ADHD group showed the usual asymmetry with left-sided hemispheric predominance in the temporal regions. The findings give further evidence for anomalous neurodevelopment with deviant hemispheric lateralization as an important factor in the aetiology of SLI. They also point to the role of subcortical structures in language impairment in childhood. Earlier focus on cortical structures in SLI research needs to be widened to include subcortical regions as well.

Intracerebral microdialysis in severe brain trauma: the importance of catheter location.

OBJECT: Intracerebral microdialysis has attracted increasing interest as a monitoring technique during neurological/neurosurgical intensive care. The purpose of this study was to compare cerebral energy metabolism, an indicator of secondary excitotoxic injury and cell membrane degradation close to focal traumatic lesions ("penumbra zones") and in remote and apparently intact brain regions of the ipsilateral and contralateral hemispheres. METHODS: The study included 22 consecutive patients with a mean age 44 +/- 17 years and an estimated postresuscitation Glasgow Coma Scale motor score less than 5. Altogether 40 microdialysis catheters with radiopaque tips were inserted. Two catheters could not be localized on postoperative computerized tomography (CT) scans and were excluded from the analysis. The perfusates were analyzed at the patient's bedside for levels of glucose, pyruvate, lactate, glutamate, and glycerol with the aid of a CMA 600 Analyzer. The positions of eight (22%) of the 36 catheters were reclassified after a review of findings on CT scans. Except for pyruvate the values of all biochemical variables and the lactate/pyruvate (L/P) ratio were significantly different in the penumbra zone when compared with mean values found in "normal" tissue ipsilateral to the parenchymal damage and in contralateral normal tissue (p < 0.001). In the penumbra zone a slow normalization of the L/P ratio and levels of glutamate and glycerol were observed. In normal tissue these parameters remained within normal limits. CONCLUSIONS: Data obtained from intracerebral microdialysis can be correctly interpreted only if the locations of the catheters as they relate to focal brain lesions are visualized. A "biochemical penumbra zone" surrounds focal traumatic brain lesions. It remains to be proven whether therapeutic interventions can protect the penumbra zone from permanent damage.

Regional cerebral blood flow (rCBF) in man during perception of radiant warmth and heat pain.

The present study concerns the effects of experimental pain (radiant warmth and heat pain) on regional cerebral blood flow (rCBF) in pretrained subjects. The radiant warmth caused a general rCBF increase. However, if anxiety was avoided, heat pain caused the general rCBF level to return towards the level at rest. Thus, pain sensation per se may not cause a larger rCBF (and metabolic) response than that of the localized tactile stimulation, provided that the element of psychic apprehension and anxiety is eliminated or controlled.

Impulsivity related to brain serotonin transporter binding capacity in suicide attempters.

Altered monoaminergic activity has earlier been associated with violent suicidal behaviour. In this study whole brain binding potential of the serotonin transporter (5HTT) and dopamine transporter (DAT) was measured by single photon emission computerised tomography (SPECT) in 12 patients after a serious suicide attempt and in 12 age, sex and season matched healthy controls. Clinical and temperamental assessments were analysed for possible associations with 5HTT and DAT. We found no significant 5HTT or DAT differences between patients and controls. In patients, but not in controls, there was a significant correlation between whole brain 5HTT and DAT. Impulsiveness according to the Marke Nyman Temperament (MNT) was significantly correlated to 5HTT in suicide attempters, but not in controls. Neither of the transporters could be regarded as a marker for serious suicidal behaviour. A previously discussed connection between serotonin and dopamine was replicated in this study. In suicide attempters, low 5HTT was associated with impulsivity and to some extent with depressive disorder-key factors for suicidal behaviour.

Transcranial Doppler sonography pulsatility index (PI) reflects intracranial pressure (ICP).

BACKGROUND: In patients with intracranial pathology, especially when comatose, it is desirable to have knowledge of the intracranial pressure (ICP). To investigate the relationship between ICP and transcranial Doppler (TCD) derived pulsatility index (PI) in neurosurgical patients, a prospective study was performed on patients admitted to our neurointensive care unit. METHODS: Daily TCD mean flow velocity (mFV) measurements were made. TCD measurements were routinely performed bilaterally on the middle cerebral artery (MCA). PI (peak systolic-end diastolic velocities/mean flow velocity) was calculated. RESULTS: Eighty-one patients with various intracranial disorders who had an intraventricular catheter for registration of the ICP were investigated: 46 (57%) patients had subarachnoid hemorrhage, 21 (26%) patients had closed head injury, and 14 (18%) patients had other neurosurgical disorders. A total of 658 TCD measurements were made. ICP registrations were made parallel with all TCD measurements. A significant correlation (p < 0.0001) was found between the ICP and the PI with a correlation coefficient of 0.938: ICP = 10.93 x PI - 1.28. In the ICP interval between 5 to 40 mm Hg the correlation between ICP and PI enabled an estimation of ICP from the PI values with an SD of 2.5. The correlation between the cerebral perfusion pressure (CPP) and PI was significant (p < 0.0001) with a correlation coefficient of -0.493. When separating the measurements in severely elevated (>120 cm/s) and subnormal (<50 cm/s) TCD mFV values, the correlation coefficient between ICP and PI was 0.828 (p < 0.002) and 0.942 (p < 0.638), respectively. CONCLUSIONS: Independent of the type of intracranial pathology, a strong correlation between PI and ICP was demonstrated. Therefore, PI may be of guiding value in the invasive ICP placement decision in the neurointensive care patient.

A new automated method for analysis of rCBF-SPECT images based on the active-shape algorithm: normal values.

Most nuclear medicine clinicians use only visual assessment when interpreting regional cerebral blood flow (rCBF) from single-photon emission computed tomography (SPECT) images in clinical practice. The aims of this study were to develop a new, easy to use, automated method for quantification of rCBF-SPECT and to create normal values by using the method on a normal population. We developed a 3-dimensional method based on a brain-shaped model and the active-shape algorithm. The method defines the surface shape of the brain and then projects the maximum counts 0-1.5 cm deep for designated surface points. These surface projection values are divided into cortical regions representing the different lobes and presented relative to the whole cortex, cerebellum or cerebellar maximum. (99m) Tc-hexa methyl propylene amine oxime (HMPAO) SPECT was performed on 30 healthy volunteers with a mean age of 74 years (range 64-98). The ability of the active-shape algorithm to define the shape of the brain was satisfactory when visually scrutinized. The results of the quantification show rCBF values in the frontal, temporal and parietal lobes of 87-88% using cerebellum as the reference. There were no significant differences in normal rCBF values between male and female subjects and only a weak relation between rCBF and age. In conclusion, our new automated method was able to quantify rCBF-SPECT images and create normal values in ranges as expected. Further studies are needed to assess the clinical value of this method and the normal values.

Genetic variation in brain-derived neurotrophic factor is associated with serotonin transporter but not serotonin-1A receptor availability in men.

BACKGROUND: The serotonergic system, including the serotonin transporter (5-HTT), which is the target of many antidepressants, seems to be influenced by brain-derived neurotrophic factor (BDNF). METHODS: Positron emission tomography (PET) was used to address, in 25 and 53 healthy volunteers, respectively, the possible association between six polymorphisms in the gene encoding BDNF and the availability of two proteins expressed by serotonergic neurons: the 5-HTT, measured with the radioligand [(11)C]MADAM, and the serotonin-1A (5-HT1A) receptor, measured with [(11)C]WAY-100635. RESULTS: Several single nucleotide polymorphisms were associated with [(11)C]MADAM binding potential (BP) in most brain regions, male carriers of the valine/valine genotype of the Val66Met polymorphism displaying higher availability. Effect sizes ranged from a 50% to a threefold increase. In contrast, there was no association for [(11)C]WAY-100635 BP. The observation that BDNF polymorphisms were associated with 5-HTT availability could be partly replicated in an independent population comprising nine male suicide attempters and nine matched control subjects, in which transporter availability had been measured with single photon emission computed tomography with (123)I-beta-CIT as ligand. CONCLUSIONS: Our results suggest that genetic variation in BDNF influences 5-HTT but not 5-HT1A receptor density in the human brain.

The role of dopamine and serotonin in suicidal behaviour and aggression.

Serotonin and dopamine are two monoamines which are known to interact with each other. Their role for suicidal behaviour, aggression and mood are reviewed in this chapter. We found a substantial amount of evidence for the relevance of a serotonin and dopamine model of aggression, and for aggression as a major risk factor for suicide. Evidence was found that serotonin and dopamine also may be involved in depressed mood, and possibly the individual's ability to cope with imminent suicidality.

Cerebral glucose metabolism and early EEG/aEEG in term newborn infants with hypoxic-ischemic encephalopathy.

The objective was to investigate how early electrocortical background pattern, as recorded with amplitude integrated EEG (aEEG), correlates with global and regional cerebral glucose metabolism (CMRgl) measured by positron emission tomography during the subacute phase after birth asphyxia. Nineteen term infants with hypoxic-ischemic encephalopathy were investigated. The aEEG background was evaluated at 0-6, 6-12, 12-24, 24-48, and 48-72 h postnatal age, and classified into four categories according to increasing degree of abnormality. The aEEG were also evaluated for sleep-wake cycling and epileptic seizure activity. CMRgl was measured by positron emission tomography with 2-(18F) fluoro-2-deoxy-d-glucose at a median (range) postnatal age 10 (4-24) d. Increasing degree of abnormality in aEEG correlated significantly with decreasing CMRgl: at 6-12 h (-0.593; 0.012) (r value; p value), 12-24 h (-0.669; 0.003), and 24-48 h (-0.569; 0.014) postnatal age. Presence of sleep-wake cycling at 0-6 h (0.697; 0.012), 6-12 h (0.668; 0.003), and 12-24 h (0.612; 0.009) of age correlated with increased CMRgl. Delayed seizure activity at 12-24 h correlated with decreased CMRgl (-0.661; 0.004). Infants with abnormal aEEG at 6-12 h had lower CMRgl in all regions of the brain compared with infants with normal aEEG. CMRgl of any specific region of the brain was not significantly more correlated to aEEG than CMRgl of other regions. Early electrocortical background patterns, early presence of sleep-wake cycling, and delayed seizure activity were highly correlated with global CMRgl measured during the subacute phase after asphyxia, but did not correlate with any specific pattern of regional uptake.

A new model for separation between brain dopamine and serotonin transporters in 123I-beta-CIT SPECT measurements: normal values and sex and age dependence.

123I-beta-CIT is a radioactive ligand for single-photon emission computed tomography (SPECT) imaging of the pre-synaptic (transporter) re-uptake sites for dopamine (DAT) and serotonin (5HTT), and it is widely used to visualize monoamine turnover. Since 123I-beta-CIT uptake occurs at 5HTT and DAT sites in conjunction with the presence of freely soluble 123I-beta-CIT in brain tissue, adequate separation of these three components is necessary. However, only partial separation is possible with current methods. Two main strategies have previously been used for 123I-beta-CIT component separation, based on the following considerations: (1) the faster uptake rate for 5HTT compared with DAT enables temporal separation by performing 5HTT imaging at 1-2 h and DAT imaging at 20-24 h; (2) blocking the 5HTT re-uptake with citalopram renders 123I-beta-CIT imaging DAT (non-5HTT) specific. In a new analytical model, we combined these two approaches with methods to isolate the passively dissolved 123I-beta-CIT in brain tissue from the monoamine transporter uptake, and to correct the 5HTT and DAT values for concomitant uptake. The new analytical model was used to study brain 5HTT and DAT in 23 normal subjects, with the aim of clarifying the effect of age and sex. A significant correlation between 5HTT and DAT values was found only in the thalamus, indicating successful component separation. Negative correlations between age and DAT were found for basal ganglia, thalami, brain stem and temporal lobes, but not for the frontal, parietal or occipital regions. No correlation with age was found for 5HTT. We found no sex difference for 5HTT or DAT.