Given Chapter 1’s findings that patient registration is significantly responsive to changes in application fees and evidence that youth consumption of addictive goods is more price-elastic than adult consumption,11 this policy could maximize cannabis access for older adults while minimizing spillovers to youths. Increasing entry costs for younger adult users may have beneficial multiplier effects if adolescent access to legal supply is driven by diversion from younger adult consumers. A few limitations of these calculations deserve mention. Since the legal market for marijuana is studied at early stages of its development, prior to market “saturation”,12 the calculations from Table 3.9 have limited external validity. There are also a number of other potential externalities that may be affected by increased marijuana access and are likely to be concentrated among youths and young adults. Future work will examine long-term effects such as dependence, human capital accumulation, and health outcomes. Given the effects found for youths, it will be particularly important for future research to track these younger cohorts as they age. Medical marijuana laws and commercial legalization are relatively recent policies, and efforts should be taken to collect more accurate and detailed data on prices and transactions in order to assess contemporaneous and longer term effects of supply changes in the legal market. Functional magnetic resonance imaging provides a non-invasive method to study human brain function. It has been used in a myriad of applications,indoor grow rack from presurgical planning for the removal of mass lesions adjacent to eloquent cortex to studying the pathophysiology of cognitive disorders such as Alzheimer’s disease .
More sensational uses for fMRI include lie detection and mind reading . This neuroimaging technique involves the rapid acquisition of many MRI brain images over time. Typical experiments have a spatial resolution on the order of a few millimeters and a temporal resolution of a few seconds. Functional MRI is thus able to provide better spatial and temporal resolution than its predecessor in neuroimaging, positron emission tomography , without depositing any harmful radiation. In addition, it can easily access subcortical structures in the brain as opposed to electroctroencephalogaphy , which is limited to the cortex. However, unlike EEG which is directly linked to neural activation, fMRI provides only an indirect measure of neural activity as it reflects hemodynamic changes that are related to brain activity. This imaging technique’s dependence on vascular factors can be a challenge in the interpretation of fMRI studies. The blood oxygenation level dependent signal phenomenon was first observed by Ogawa and colleagues in the early 1990s and has since become the most common fMRI technique. As its name suggests, BOLD fMRI depends on the oxygen content in the blood. This is because hemoglobin, which transports oxygen, contains iron. In its deoxygenated state, the molecule becomes paramagnetic and disrupts the fMRI signal around blood vessels. As a result, the fMRI signal is reduced when the blood contains more deoxyhemoglobin, and increased when it contains less. During a task such as finger tapping there is a local increase in neuronal activity and consequent oxygen metabolism , which increases deoxyhemoglobin content in that region. However, accompanying neural activity is a regional increase in cerebral blood flow and cerebral blood volume due to vasodilatation.
The increase in CBF actually overcompensates for the local oxygen demand and results in an excess of oxygenated blood at the local site. As a result, there is an overall increase in the BOLD signal in the region of neural activity. The sequence of events that gives rise to BOLD signal generation is illustrated in Figure 1.2.Arterial spin labeling is an fMRI technique that directly targets CBF changes that follow neural activity. This is done by applying a magnetic inversion pulse to the fMRI signal in the blood flowing into the brain. Over time, as the blood flows up into the imaging plane, the MR signal will slowly recover but not fully and thus when an image is acquired there will be a loss of signal. Interleaved with tag images, control images are acquired in which the MR signal in the blood is not inverted and thus contributes entirely to the image. The difference between the tag and control images is proportional to CBF, and thus measurements of CBF can be obtained. The ASL imaging procedure is depicted in Figure 1.3. ASL fMRI is advantageous to BOLD fMRI because it directly and quantitatively measures a single physiological variable . In addition, ASL provides better spatial localization of neural activity because it is sensitive to arteries while the BOLD signal is more prominent near draining veins . However, ASL suffers from a low signal to noise ratio because in flowing blood comprises only about 1% of each voxel being imaged. ASL fMRI is also more technically challenging to implement, and cannot achieve the same brain coverage or temporal resolution as BOLD fMRI . Traditionally, fMRI studies have measured the brain’s response to controlled stimuli . Changes in the fMRI signal that are correlated with the stimulus presentation over time are then interpreted as neural responses.
However, specific task demands actually account for as little as 5% of the brain’s total energy budget , suggesting that intrinsic activity may be far more significant than evoked activity in terms of overall brain function. Biswal and colleagues first discovered that the seemingly random BOLD fluctuations that occur during resting state are actually correlated within specific functional networks such as the motor cortex , as shown in Figure 1.4. Since this discovery, there has been an exponential growth in the number of published studies examining this so-called resting-state functional connectivity. Resting-state studies are easy to implement, making them especially useful for patient populations unable to perform complicated tasks. Furthermore, differences in connectivity have shown promise in assessing disease and predicting cognitive performance . While resting-state studies may provide very useful information, caution needs to be used in the interpretation of differences in BOLD connectivity, as the BOLD signal is an indirect measure of neural activity and also depends on vascular factors. A number of studies have shown that vascular differences contribute to variability in the task-related BOLD response . For example, Cohen and colleagues showed that a hypercapnic increase in baseline CBF led to a slower and smaller BOLD response, while a hypocapnic decrease in baseline CBF led to a faster and larger BOLD response . In this study, it was assumed that the small changes in end-tidal CO2 caused by breathing 5% CO2 or by hyperventilating would not produce any changes in neural activity or CMRO2, and thus the BOLD changes were purely vascular. Previous work by our group has also shown that inter-subject differences in the task-related BOLD response amplitude are correlated with baseline CBF,ebb and flow system again suggesting that vascular differences are responsible for BOLD differences in healthy subjects . It is possible that resting-state BOLD metrics may also be sensitive to differences in baseline CBF. Since many diseases and pharmacological agents are known to alter the vasculature, this is an important potential confound to investigate.Caffeine is a widely consumed stimulant that can be used to alter subjects’ blood flow and test for resulting changes in resting-state functional connectivity. By inhibiting adenosine binding to receptors on smooth muscles cells, caffeine reduces the ability of blood vessels to dilate and causes an overall reduction in baseline CBF . Previous studies by our research group and have shown that caffeine increases the speed of the visual BOLD response , suggesting that the BOLD signal is more sensitive to neural activity during caffeine-induced vasoconstriction.The purpose of this work was to determine whether resting-state BOLD measures are modulated by inter-subject differences in baseline CBF or vasoactive sub-stances such as caffeine. If so, this vascular dependence can be a confound in the interpretation of functional connectivity differences found in disease or cognitive ability. In our first study, we examined the effect of caffeine on resting-state BOLD connectivity in the motor cortex across a sample of 9 healthy subjects.
In the second study we used a sliding window approach to investigate the stationarity of caffeine’s effect on BOLD connectivity. We found that BOLD correlation was significantly more variable over time following a caffeine dose, and that strong periods of correlation still existed between periods of lower correlation. Furthermore, the temporal variability of BOLD signal correlation was driven by phase differences between the BOLD signals in the left and right motor cortices. In the third study we investigated the BOLD signal dependence on inter-subject differences in baseline CBF using a sample of 17 healthy subjects. We acquired simultaneous BOLD and CBF measures during a motor task and resting-state. Consistent with prior studies, we found a strong dependence of the task-evoked BOLD response on inter-subject variations in baseline CBF, but found a much weaker and not significant dependence of the resting-state BOLD response on baseline CBF. In addition, inter-hemispheric resting-state BOLD connectivity between motor cortex regions did not show a significant dependence on baseline CBF. We demonstrate that these findings reflect a reduced ratio between CBF changes and oxygen metabolism during the resting state, as compared to the task-evoked condition.In resting-state functional magnetic resonance imaging , low-frequency fluctuations in the blood oxygenation level dependent signal are generally thought to reflect underlying fluctuations in neural activity. The correlation between BOLD fluctuations in different brain regions is then used as a measure of functional connectivity between these regions. A change in BOLD correlation is often interpreted as a change in the functional connectivity of the respective brain regions. Biswal and colleagues were the first to demonstrate the presence of synchronous BOLD fluctuations within the motor cortex at rest. Since then, resting-state connectivity has been evaluated in many other functional networks including the default mode network, which comprises regions of the brain that routinely decrease activity in the presence of a task . The strength of functional connections in the default mode network has been shown to correlate with performance on working memory tasks , providing evidence that spontaneous activity can yield important information regarding cognitive ability and function. Also, a growing number of studies have demonstrated that resting-state connectivity is altered in disorders such as Alzheimer’s disease, schizophrenia, multiple sclerosis, and epilepsy . In these studies, decreases in BOLD connectivity are often interpreted as an impairment of the neural connections between related brain regions. However, this interpretation can be complicated by the dependence of the BOLD signal on both neural and vascular factors. Functional MRI provides an indirect measure of neural activity, where the BOLD response is a complex function of changes in oxygen metabolism, cerebral blood flow , and blood volume that follow changes in neural activity . As a result, the BOLD signal may be affected by alterations in the neurovascular coupling that links neural activity to hemodynamic changes. Studies with task-related BOLD fMRI have shown that changes in neurovascular coupling, due to factors such as disease, age, medication, and diet, can significantly alter the BOLD response . In particular, factors that alter baseline CBF can modulate the temporal dynamics of the BOLD response through alterations in the strength of neurovascular coupling . Hypercapnia, which increases baseline CBF through vasodilation, has been shown to reduce the magnitude and speed of the visual BOLD response . These changes indicate that the BOLD response may be less sensitive to neural stimulation when baseline CBF is increased. Additional studies by our research group and others have shown that caffeine and hypocapnia, which both reduce baseline CBF, increase the speed of the visual BOLD response , suggesting that neurovascular coupling is strengthened when CBF decreases. The amplitude of the task-related BOLD response has also been shown to have an inverse dependence on baseline CBF , both across subjects and pharmacological conditions. Overall, these studies suggest that the sensitivity of the BOLD response to stimulated neural activity may be inversely related to baseline CBF. Changes in neurovascular coupling may also influence resting-state BOLD connectivity measures. A number of studies have examined the effect of altered baseline CBF on low-frequency fluctuations in cerebral hemodynamics . For example, Dirnagl et al. found that nitrous oxide synthase blockade, which constricts blood vessels, produced an increase in low-frequency oscillations in CBF as measured with laser-Doppler flowmetry in rats anaesthetized with α-chloralose. In another study of anaesthetized rats, Hudetz et al. showed that nitrous oxide synthase blockade increased flow oscillations, while hypercapnia reduced the oscillations.