Maternal SSRI exposure increases the risk of autistic offspring: A meta-analysis and systematic review.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the most common antidepressants used to preclude maternal pregnancy depression. There is a growing body of literature assessing the association of prenatal exposure to SSRIs with autism spectrum disorder (ASD). The present systematic review and meta-analysis reviewed the medical literature and pooled the results of the association of prenatal exposure to SSRIs with ASD. METHODS: Published investigations in English by June 2016 with keywords of selective serotonin reuptake inhibitors, SSRI, autism spectrum disorder, ASD, pregnancy, childhood, children, neurodevelopment were identified using databases PubMed and PMC, MEDLINE, EMBASE, SCOPUS, and Google Scholar. Cochran's Q statistic-value (Q), degree of freedom (df), and I2 indices (variation in odds ratio [OR] attributable to heterogeneity) were calculated to analyze the risk of heterogeneity of the within- and between-study variability. Pooled odds ratio (OR) and 95% confidence interval (CI) were reported by a Mantel-Haenszel test. RESULTS: There was a non-significant heterogeneity for the included studies ([Q=3.61, df=6, P=0.730], I2=0%). The pooled results showed a significant association between prenatal SSRI exposure and ASD (OR=1.82, 95% CI=1.59-2.10, Z=8.49, P=0.00). CONCLUSION: The evidence from the present study suggests that prenatal exposure to SSRIs is associated with a higher risk of ASD.

Mitochondrial DNA G13708A variation and multiple sclerosis: Is there an association?

BACKGROUND: Multiple sclerosis (MS) is considered a pathogenetic enigma. Recently, efforts to implicate genetics in human susceptibility to MS have identified an important role of mitochondrial DNA (mtDNA). G13708A is a common mtDNA variation associated with MS in specific populations. This study tested the hypothesis that the mtDNA G13708A variation is associated with MS in an Iranian population. MATERIALS AND METHODS: Blood samples were collected from 100 MS patients and 100 unrelated healthy controls. DNA was extracted using a salting-out method, followed by polymerase chain reaction (PCR) amplification. For assessment of restriction fragment length polymorphism (RFLP), PCR products were restricted by restriction enzyme Mva I. Thereafter, the restriction products were assessed by means of an ultraviolet (UV) transilluminator following electrophoresis with 3% agarose gel. Accuracy of the genotyping procedure was assessed by direct sequencing. RESULTS: The mtDNA G13708A variation was found in 17 cases (17%) and 19 controls (19%) (P=0.7, OR: 0.8, 95% CI: 0.3-1.9). CONCLUSION: The findings of the present study fail to support the hypothesis that the G13708A mtDNA variation is associated with MS in the selected Iranian population.

Regional cerebral blood flow responses to hyperventilation during sevoflurane anaesthesia studied with PET.

BACKGROUND: Arterial carbon dioxide tension (PaCO(2)) is an important factor controlling cerebral blood flow (CBF) in neurosurgical patients. It is still unclear whether the hypocapnia-induced decrease in CBF is a general effect on the brain or rather linked to specific brain regions. We evaluated the effects of hyperventilation on regional cerebral blood flow (rCBF) in healthy volunteers during sevoflurane anaesthesia measured with positron emission tomography (PET). METHODS: Eight human volunteers were anaesthetized with sevoflurane 1 MAC, while exposed to hyperventilation. During 1 MAC sevoflurane at normocapnia and 1 MAC sevoflurane at hypocapnia, one H(2)(15)O scan was performed. Statistical parametric maps and conventional regions of interest analysis were used for estimating rCBF differences. RESULTS: Cardiovascular parameters were maintained constant over time. During hyperventilation, the mean PaCO(2) was decreased from 5.5 + or - 0.7 to 3.8 + or - 0.9 kPa. Total CBF decreased during the hypocapnic state by 44%. PET revealed wide variations in CBF between regions. The greatest values of vascular responses during hypocapnia were observed in the thalamus, medial occipitotemporal gyrus, cerebellum, precuneus, putamen and insula regions. The lowest values were observed in the superior parietal lobe, middle and inferior frontal gyrus, middle and inferior temporal gyrus and precentral gyrus. No increases in rCBF were observed. CONCLUSIONS: This study reports highly localized and specific changes in rCBF during hyperventilation in sevoflurane anaesthesia, with the most pronounced decreases in the sub cortical grey matter. Such regional heterogeneity of the cerebral vascular response should be considered in the assessment of cerebral perfusion reserve during hypocapnia.

Effects of dose-dependent levels of isoflurane on cerebral blood flow in healthy subjects studied using positron emission tomography.

BACKGROUND: In this study, we tested the hypothesis that escalating drug concentrations of isoflurane are associated with a significant decline in cerebral blood flow (CBF) in regions sub-serving conscious brain activity, including specifically the thalamus. METHODS: Nine human volunteers received three escalating drug concentrations: 0.2, 0.4 and 1.0 MAC end-tidal inhalation. During waking, baseline and the three levels of sedation, aO PET scan was performed. RESULTS: Isoflurane decreased the bispectral index (BIS) values dose-dependently. Cardiovascular and respiratory parameters were maintained constant over time. No significant change in global CBF was observed. Throughout all three MAC levels of sedation, isoflurane caused an increased regional cerebral blood flow (rCBF) in the anterior cingulate and decreased rCBF in the cerebellum. Initially, isoflurane (0 vs. 0.2 MAC) significantly increased relative rCBF in the medial frontal gyrus and in the nucleus accumbens. At the next level (0.2 vs. 0.4 MAC), relative rCBF was significantly increased in the caudate nucleus and decreased in the lingual gyrus and cuneus. At the last level (0.4 vs. 1 MAC), relative rCBF was significantly increased in the insula and decreased in the thalamus, the cuneus and lingual gyrus. Compared with flow distribution in awake volunteers, 1 MAC of isoflurane significantly raised relative activity in the anterior cingulate and insula regions. In contrast, a significant relative flow reduction was identified in the thalamus, the cerebellum and lingual gyrus. CONCLUSIONS: Isoflurane, like sevoflurane, induced characteristic flow redistribution at doses of 0.2-1.0 MAC. At 1 MAC of isoflurane, rCBF decreased in the thalamus. Specific areas affected by both isoflurane and sevoflurane included the anterior cingulate, insula regions, cerebellum, lingual gyrus and thalamus.

Effects of subanaesthetic and anaesthetic doses of sevoflurane on regional cerebral blood flow in healthy volunteers. A positron emission tomographic study.

BACKGROUND: We tested the hypothesis that escalating drug concentrations of sevoflurane are associated with a significant decline of cerebral blood flow in regions subserving conscious brain activity, including specifically the thalamus. METHODS: Nine healthy human volunteers received three escalating doses using 0.4%, 0.7% and 2.0% end-tidal sevoflurane inhalation. During baseline and each of the three levels of anaesthesia one PET scan was performed after injection of . Cardiovascular and respiratory parameters were monitored and electroencephalography and bispectral index (BIS) were registered. RESULTS: Sevoflurane decreased the BIS values dose-dependently. No significant change in global cerebral blood flow (CBF) was observed. Increased regional CBF (rCBF) in the anterior cingulate (17-21%) and decreased rCBF in the cerebellum (18-35%) were identified at all three levels of sedation compared to baseline. Comparison between adjacent levels sevoflurane initially (0 vs. 0.2 MAC) decreased rCBF significantly in the inferior temporal cortex and the lingual gyrus. At the next level (0.2 MAC vs. 0.4 MAC) rCBF was increased in the middle temporal cortex and in the lingual gyrus, and decreased in the thalamus. At the last level (0.4 MAC vs. 1 MAC) the rCBF was increased in the insula and decreased in the posterior cingulate, the lingual gyrus, precuneus and in the frontal cortex. CONCLUSION: At sevoflurane concentrations at 0.7% and 2.0% a significant decrease in relative rCBF was detected in the thalamus. Interestingly, some of the most profound changes in rCBF were observed in structures related to pain processing (anterior cingulate and insula).

Focal changes of oxygen consumption in cerebral cortex of patients with Parkinson's disease during subthalamic stimulation.

Motor symptoms of Parkinson's disease (PD) are substantially improved by bilateral high-frequency electrical stimulation of the subthalamic nucleus (STN). Altered cerebral blood flow (CBF) in a network of frontal cortical and subcortical structures has been reported in numerous studies of patients undergoing subthalamic stimulation. However, CBF is a controversial indicator of brain activation because measures of blood flow bear a variable relation to measures of brain work and energy metabolism. We hypothesized that STN stimulation would alter the rate of oxygen consumption (CMRO(2)) in cerebral cortical areas in proportion to previously reported changes in CBF in patients undergoing stimulation at rest. We used quantitative PET to map CMRO(2) in brain of seven patients with Parkinson's disease, first in a baseline condition with pause of stimulation and medication for a period of 12 h, and again after 4 h of stimulation. Comparison of these two conditions revealed activation of CMRO(2) in the cerebellum, and in specific posterior neocortical regions, most notably in the left lingual gyrus and in the right lateral occipitotemporal gyrus, both of which latter regions are linked to higher-order visual processing. CMRO(2) was unaffected in the frontal cortex. Thus, the present findings do not support the original hypothesis, but suggest that STN stimulation increases energy metabolism in the posterior cerebral cortex, especially in regions involved in perception of movement and the direction of movement to visual cues.

Impaired activation of oxygen consumption and blood flow in visual cortex of patients with mitochondrial encephalomyopathy.

A current hypothesis claims that an increase of blood flow is required for oxygen consumption to rise during neuronal excitation (activation). Chronic progressive external ophthalmoplegia is a mitochondrial disease associated with deletions of mtDNA or by point mutation of tRNA genes. We tested the hypothesis that the cerebral metabolic rate of oxygen (CMRO2) may not rise in this disorder if the accompanying cerebral blood flow increase is insufficient. Two patients with progressive external ophthalmoplegia were visually stimulated with a colored checkerboard pattern reversing as different frequencies. When stimulated, Patient 1 had a small increase of cerebral blood flow, while Patient 2 had no cerebral blood flow increase. In the visually active state, the patients had no significant change of CMRO2, while healthy subjects had a pronounced increase of CMRO2 in the pericalcarine visual cortex at 4 Hz and a further slight increase at 8 Hz during activation.

Model of blood-brain transfer of oxygen explains nonlinear flow-metabolism coupling during stimulation of visual cortex.

The coupling between cerebral metabolic rate of oxygen (CMRO2) and blood flow (CBF) in response to visual stimulation was evaluated by means of a model of oxygen delivery. The model predicted a nonlinear relationship between stimulus-evoked changes of oxygen consumption and blood flow. The magnitude of the CMRO2/CBF ratio index (IO2) was used to indicate the degree of flow-metabolism coupling prevailing in specific areas of the brain during physiological stimulation. Therefore, the index provided a measure of the blood oxygenation level dependent (BOLD) magnetic resonance contrast. To evaluate the changes of IO2 in response to visual stimulation, the model was applied to the effect of a changing flicker rate of a visual stimulus on the magnitudes of CBF, CMRO2, and oxygen diffusion capacity, in the human brain. Positron emission tomography (PET) was used to measure the CBF and the CMRO2 in 12 healthy volunteers who viewed a cross-hair (baseline) or a yellow-blue annular checkerboard reversing at frequencies of 1, 4, or 8 Hz. The magnitude of CBF in the primary visual cortex increased as a function of the checkerboard reversal rate and reached a maximum at the frequency of 8 Hz (z=16.0), while the magnitude of CMRO2 reached a maximum at 4 Hz (z=4.0). Therefore, the calculated IO2 was lower at 8 Hz than at 1 and 4 Hz, in contrast to the oxidative metabolic rate that reached its maximum at 4 Hz. The model explained the increase of oxygen consumption as the combined effect of increased blood flow and increased oxygen diffusion capacity in the region of visual activation.

Frequency-dependent changes in cerebral metabolic rate of oxygen during activation of human visual cortex.

To test the hypothesis that brain oxidative metabolism is significantly increased upon adequate stimulation, we varied the presentation of a visual stimulus to determine the frequency at which the metabolic response would be at maximum. The authors measured regional CMR(O2) in 12 healthy normal volunteers with the ECAT EXACT HR+ (CTI/Siemens, Knoxville, TN, U.S.A.) three-dimensional whole-body positron emission tomograph (PET). In seven successive activating conditions, subjects viewed a yellow-blue annular checkerboard reversing its contrast at frequencies of 0, 1, 4, 8, 16, 32, and 50 Hz. Stimulation began 4 minutes before and continued throughout the 3-minute dynamic scan. In the baseline condition, the subjects began fixating a cross hair 30 seconds before the scan and continued to do so for the duration of the 3-minute scan. At the start of each scan, the subjects inhaled 20 mCi of (15)O-O2 in a single breath. The CMR(O2) value was calculated using a two-compartment, weighted integration method. Normalized PET images were averaged across subjects and coregistered with the subjects' magnetic resonance imaging in stereotaxic space. Mean subtracted image volumes (activation minus baseline) of CMR(O2) then were obtained and converted to z statistic volumes. The authors found a statistically significant focal change of CMR(O2) in the striate cortex (x = 9; y = -89; z = -1) that reached a maximum at 4 Hz and dropped off sharply at higher stimulus frequencies.

Increased oxygen consumption in human visual cortex: response to visual stimulation.

To test whether a sufficiently complex visual stimulus causes the consumption of oxygen to rise in the human visual cortex, we used positron emission tomography (PET) to measure the cerebral metabolic rate of oxygen (CMRO2) during visual stimulation in 6 healthy normal volunteers. A yellow-blue checkerboard, reversing its contrast at a frequency of 8 Hz, was presented for a period of 7 min, beginning 4 min before the onset of a 3-min scan. In the baseline condition, subjects fixated a cross-hair from 30 s before until the end of the 3-min scan. The CMRO2 was calculated with the two-compartment weighted integration method (1). The checkerboard minus baseline subtraction yielded statistically significant increases in CMRO2 in the primary (V1) and higher order visual cortices (V4 and V5). The significant CMRO2 increases were detected in these regions in both the group average and in each individual subject.