Medial surface of left cerebral hemisphere The

Medial surface of left cerebral hemisphere

The basis of the MEG signal The magnetic field of the brain for cortical activity and for the human alpha rhythm is of 10 f. T (1 femtotesla= 10 -15) & 103 f. T, correspondently vs. the ambient magnetic noise in an urban environment, which is on the order of 108 f. T. Solution: SQUIDs + Magnetic shielding

Squid Magnetometer Schematic of a first order axial gradiometer consisting of two oppositely wound coils inductively coupled to the SQUID sensor

Recording and displaying of magnetoencephalographic rhythms. The subject sits in a magnetically shielded room, with his head under a whole-scalp neuromagnetometer

The MEG origin. q The MEG (and EEG) signals derive from the net effect of ionic currents flowing in the dendrites of neurons during synaptic transmission. In accordance with Maxwell's equations, any electrical current will produce an orthogonally oriented magnetic field. It is this field which is measured with MEG. q The net currents can be thought of as current dipoles which are currents defined to have an associated position, orientation, and magnitude, but no spatial extent. According to the righthand rule, a current dipole gives rise to a magnetic field that flows around the axis of its vector component. q In order to generate a signal that is detectable, approximately 50, 000 active neurons are needed.

Magnetic source image (MSI) § Usually, lipid markers (e. g. vitamin pills) are attached on these three fiducial points, and a structural MRI is taken, either before or after the MEG recording session. The positions of the markers are visible on the MRI scans. § Therefore, the relative position of all brain structures with respect to the position of the source of activity is also known. § The position of the source or sources can be projected onto the appropriate MRI slices resulting in composite images. Thus, the locations of these activity sources are estimated and projected onto the structural images of the brain (MRI) creating the magnetic source image (MSI), which displays the activated brain regions.

Magnetic source image (MSI) Thus, MEG consists of 1) recording magnetic flux on the head surface associated with electrical currents in activated neuronal aggregates modeled as equivalent current dipoles (ECDs); 2) estimating the location of such sets, referred to as activity sources or event-related fields (ERFs); and 1) projecting the ERFs onto an MRI of the brain to identify and envision the activated brain regions (MSI).

The MEG applications. Functional Mapping with MEG. In research, q MEG's primary use is the measurement of time courses of activity, as such time courses cannot be measured using functional magnetic resonance imaging (f. MRI). q MEG also accurately pinpoints sources in primary auditory, somatosensory and motor areas, whereas its use in creating functional maps of human cortex during more complex cognitive tasks is more limited. Focal Epilepsy and brain tumor. q The clinical uses of MEG are in detecting and localizing epileptiform spiking activity in patients with epilepsy, and in localizing eloquent cortex for surgical planning in patients with brain tumors or intractable epilepsy. q The goal of epilepsy surgery is to remove the epileptogenic tissue while sparing essential brain areas to avoid neurologic deficits. Knowing the exact position of essential brain regions (such as the primary motor cortex and primary sensory cortex, visual cortex, and speech cortex) is of utmost importance. ----------------q Direct cortical stimulation and somatosensory evoked potentials recorded on ECo. G are considered the gold standard for localization of essential brain regions. These procedures can be performed either intraoperatively or from chronically indwelling subdural grid electrodes; however, they are both invasive to the patient. q MEG localizations of the central sulcus obtained from somatosensory evoked magnetic fields show strong agreement with these invasive recordings (a correlation of 4 to 10 mm between the MEG sources and the ECo. G stimulation localization).

Average evoke responses to auditory and visual stimuli. le sensory and the latter of higher functions. The evoked responses consist of early (up to 150 ms) and late components. The former correspond to activation of the sensory cortex specific to each type of stimulus and the latter, typically, to activation of the association cortex. That is, the former enable identification of the mechanism of simple sensory and the latter of higher functions.

Typical MEG images displaying signs of the mechanisms of the visual auditory and somatosensory functions. Each symbol represents the computed source location of the averaged magnetic flux recorded at a given point in time after the presentation of a visual, auditory or somatic stimulus. As expected, sources of visual responses are located in medial occipital cortex, and the sources of auditory responses in the superior temporal plane, bilaterally. Stimulation of each of three fingers in each hand is associated with anatomically distinct sources in the contralateral parietal lobe.

EEG vs. MEG Although EEG and MEG are generated by the same neurophysiologic processes, there are important differences concerning the neurogenesis of MEG and EEG. q In contrast to electric fields, magnetic fields are less distorted by the resistive properties of the skull and scalp, which result in a better spatial resolution of the MEG. q Whereas scalp EEG is sensitive to both radial and tangential components of a current source in a spherical volume conductor, MEG detects only its tangential components. This shows MEG selectively measures the activity in the sulci, whereas scalp EEG measures activity both in the sulci and at the top of the cortical gyri but appears to be dominated by radial sources. q Scalp EEG is sensitive to extracellular volume currents produced by postsynaptic potentials, MEG primarily detects intracellular currents associated with these synaptic potentials because the field components generated by volume currents tend to cancel out in a spherical volume conductor. q The decay of magnetic fields as a function of distance is more pronounced than for electric fields. MEG is therefore more sensitive to superficial cortical activity, which should be useful for the study of neocortical epilepsy. q Finally, MEG is reference-free which is in contrast to scalp EEG, where an active reference can lead to serious difficulties in the interpretation of the data

Transcranial magnetic stimulation (TMS) is a noninvasive method to excite neurons in the brain: weak electric currents are induced in the tissue by rapidly changing magnetic fields (electromagnetic induction). This way, brain activity can be triggered with minimal discomfort, and the functionality of the circuitry and connectivity of the brain can be studied. A brief electrical current (mcs) generates a magnetic field around the coil windings, which, in turn, induces electrical currents in the brain that flows in parallel, but opposite to those in the TMS coil.

TMS, a figure-of-eight shaped TMS coil placed on the subject’s head using a mechanical coil holder. With stereotactic MRI-based control, the precision of targeting TMS can be approximated to a few millimeters

TMS and r. TMS techniques in research TMS is important in cognitive psychology/neuroscience is that it can demonstrate causality. For ex. , f. MRI allows researchers to see what regions of the brain are activated when a subject performs a certain task, and it shows that a region is associated with a task. If activity in the associated region is suppressed (i. e. 'knocked out') with TMS stimulation and a subject then performs worse on a task, this is much stronger evidence that the region is used in performing the task. This ‘knock-out’ technique (virtual lessoning) can be done in two ways: Online TMS: where subjects perform the task and at a specific time point (usually in the order of 1 -200 ms) of the task, a TMS pulse is given to a particular part of the brain. This should affect the performance of the task specifically, and thus demonstrate that this task involves this part of the brain at this particular time point. The advantage: § how and when the brain processes a task, § there is no time for a placebo effect or other brain areas to compensate. The disadvantages: § in addition to the location of stimulation, one also has to know roughly when the part of the brain is responsible for the task so lack of effect is not conclusive.

TMS and r. TMS techniques in research Offline repetitive TMS: where performance at a task is measured initially and then repetitive TMS is given over a few minutes, and the performance is measured again. This technique has the advantage of not requiring knowledge of the timescale of how the brain processes. However offline r. TMS is very susceptible to the placebo effect. Additionally, the effects of repetitive TMS are variable between subjects and also for the same subject. A variant of this technique is the ‘enhancement’ technique, where repetitive TMS is delivered to enhance performance. This is even harder to achieve than the ‘knock-out’ technique.

Computed tomography (CT) is a medical imaging method employing tomography. Digital geometry processing is used to generate a three-dimensional image of the inside of an object from a large series of two-dimensional X-ray images taken around a single axis of rotation. Many data scans are progressively taken as the object is gradually passed through the gantry.

Multislice CT Scanner: Philips 'Brilliance' 64 -channel thin-slice

CT Process X-ray slice data is generated using an X-ray source that rotates around the object; X-ray sensors are positioned on the opposite side of the circle from the X-ray source. The modern X-ray sensors - photo diodes. CT scanner with cover removed to show the principle of operation CT scan illustration

CT Process

Typical scan doses Examination Typical effective dose (m. Sv) (milli rem) Chest X-ray 0. 1 10 Head CT 1. 5 150 Screening mammography 3 300 Abdomen CT 5. 3 530 Chest CT 5. 8 580 Chest, Abdomen and Pelvis CT 9. 9 990 CT colonography (virtual colonoscopy) 3. 6 - 8. 8 360 - 880 Cardiac CT 6. 7 -13 670 - 1300 Barium enema 15 1500 Neonatal abdominal CT 20 2000 New software technology can significantly reduce the radiation dose. The software works as a filter that reduces random noise and enhances structures. In this way, it is possible to get high-quality images and at the same time lower the dose by as much as 30 to 70 percent. For comparison, survivors of the atomic bombings of Hiroshima and Nagasaki were exposed to an average of 40 m. Sv of radiation. This dose is comparable to two or three extensive CT scans, and can increase the risk of cancer.

Positron emission tomography (PET) q Positron emission tomography (PET) is a nuclear medicine imaging technique which produces a three-dimensional image or picture of functional processes in the body. q The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide (tracer), which is introduced into the body on a biologically active molecule. q Images of tracer concentration in 3 -dimensional space within the body are then reconstructed by computer analysis.

Before a PET scan begins a patient is given a safe dose of a radioactive compound emitting positrons. Commonly used are nitrogen 13, oxygen 15, carbon 11, fluorine 18 (with extra protons). If the purpose of the PET scan is to study brain activity, FDG is used to choose (fluorodeoxyglucose), which is a modified glucose molecule. The injected or inhaled FDG will enter the person's bloodstream, where it can travel to the brain. If a particular area of the brain is more active, more glucose or energy will be needed there. The more glucose is used, the more radioactive material is absorbed. FDG is a normal glucose molecule that has been attached artificially to a radioactive isotope of flourine. FDG can be absorbed by cells just like normal glucose. The PET scanner measures energy that is emitted when positrons from the radioactive material collide with electrons in the person's brain. The scan take between 30 minutes to two hours to complete. A computer then turns these measurements into multicolored two- or three-dimensional images. The result is a colorful picture showing which parts of the brain were most active, based on the amount of glucose being used there. To measure the amount of radioactive material absorbed by the brain, a person lies on a moveable bed that slides into the tunnel-like opening of a device called a PET scanner.

§ To create the colorful PET image, a computer displays each measurement as a series of tiny dots. § The color of each dot indicates the intensity of the energy that is recorded. § Red indicates the highest intensity-in other words, the area of greatest brain activity. Very High Activity Medium Activity Low Activity No Activity

GE Advance PET scanner

Micro. PET scanner

Radioisotopes Radionuclides used in PET scanning are typically isotopes with short half lives such as carbon 11(~20 min), nitrogen-13 (~10 min), oxygen-15(~2 min), and fluorine-18 (~110 min, commercial). These radionuclides are incorporated either into compounds normally used by the body such as glucose (or glucose analogues), water or ammonia, or into molecules that bind to receptors or other sites of drug action. Such labeled compounds are known as radiotracers. Due to the short half lives of most radioisotopes, the radiotracers must be produced using a cyclotron and radiochemistry laboratory that are in close proximity to the PET imaging facility. Limitations to the widespread use of PET arise from the high costs of cyclotrons needed to produce the short-lived radionuclides for PET scanning and the need for specially adapted onsite chemical synthesis apparatus to produce the radiopharmaceuticals. Few hospitals and universities are capable of maintaining such systems, and most clinical PET is supported by third-party suppliers of radiotracers which can supply many sites simultaneously. Because the half-life of F-18 is about two hours, the prepared dose of a radiopharmaceutical bearing this radionuclide will undergo multiple half-lives of decay during the working day. This necessitates frequent recalibration of the remaining dose (determination of activity per unit volume) and careful planning with respect to patient scheduling.

Accelerator for generating PET radiotracers

PET: Gamma ray detection A. The nucleus of an unstable radionuclide emits a positron which travels a certain distance before it collides with an electron and is annihilated emitting two gamma rays, which then travel in precisely opposite directions. The site of positron annihilation that is imaged may be a few mm from the site of origin. For ex. , 2 mm for F 18 & 3 mm for O 15. The distance between the emitting nucleus and the site where the positron is annihilated is an absolute limit on the spatial resolution of PET scan images. B. Gamma rays are detected by an array of cristal and photomultipliers that surround the head. Only signals that are detected simultaneously by diagonally placed photomultipliers are recorded. -----------------------------------The normal resting pattern of glucose consumption within the human brain as measured with PET and F 18 –labeled fluorodeoxyglucose. Resolution is about 3 mm. Deoxyglucose is not metabolized but accumulates in neurons , and the amount accumulated is an index of the rate of glucose metabolism, and local neuronal activity.

The Brain on Drugs When someone gets “high” on cocaine, where does the cocaine go in the brain? §The PET scan shows a person’s brain on cocaine and the area of the brain, highlighted in yellow, where cocaine is “binding” or attaching itself (minute by minute, in a time-lapsed sequence). 1 -2 Min 3 -4 5 -6 6 -7 7 -8 8 -9 §After 3 to 4 minutes, some areas starting to turn yellow. These areas are part of a brain structure called the striatum that is the main target in the brain bound activated by cocaine. §At the 5 - to 8 -minute interval, cocaine is affecting a large area of the brain. §After that, the drug’s effects begin to wear off. At the 9 - to 10 -minute point, the high feeling is almost 9 -10 gone. §Unless the abuser takes more cocaine, the experience is over in about 20 to 30 minutes. 9 -10 10 -20 20 -30 Photo courtesy of Nora Volkow, Ph. D. Mapping cocaine binding sites in human and baboon brain in vivo. Fowler JS, Volkow ND, Wolf AP, Dewey SL, Schlyer DJ, Macgregor RIR, Hitzemann R, Logan J, Bendreim B, Gatley ST. et al. Synapse 1989; 4(4): 371 -377.

The Brain After Drugs Long-term effects of drug abuse Normal Cocaine Abuser (10 days) Cocaine Abuser (100 days) Photo courtesy of Nora Volkow, Ph. D. Volkow ND, Hitzemann R, Wang C-I, Fowler IS, Wolf AP, Dewey SL. Long-term frontal brain metabolic changes in cocaine abusers. Synapse 11: 184 -190, 1992; Volkow ND, Fowler JS, Wang G-J, Hitzemann R, Logan J, Schlyer D, Dewey 5, Wolf AP. Decreased dopamine D 2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14: 169 -177, 1993.

The Memory of Drugs Front of Brain Amygdala not lit up Amygdala activated Back of Brain This slide demonstrates something really amazing—how just the mention of items associated with drug use may cause an addict to crave or desire drugs. For this study, brain scans were performed while subjects watched two videos. The first video, a nondrug presentation, showed nature images—mountains, rivers, animals, flowers, trees. The second video showed cocaine and drug paraphernalia, such as pipes, needles, matches, and other items familiar to addicts. This is how the memory of drugs works: The yellow area on the upper part of the second image is the amygdala, a part of the brain’s limbic system, which is critical for memory and responsible for evoking emotions. For an addict, when a drug craving occurs, the amygdala becomes active and a craving for cocaine is triggered. Photo courtesy of Anna Rose Childress, Ph. D.

PET in Cognitive Neuroscience 1 3 2 4 The positron emission tomography (PET) scan on the left shows typical patterns of brain activity associated with: • Reading words 1 • Hearing words 2 • Thinking about words 3 • Saying words 4 Activity is highest in red areas and then decreases through the other colors of the rainbow from yellow to blue-violet.

Positron emission tomography (PET) § The brain areas which are activated either hemodynamically or metabolically are visualized as increased signal (oxygen-15 accumilation). § The obtained image provides the time information of the order of minutes. Rat brain § Image quality improvement as a result of increased spatial resolution in animal PET over the last decade. § gold standard’: [ C]CFT in vitro autoradiography on a 15 mm horizontal section of rat brain, showing the true shape of the striatal region. s—striata, c—cerebellum, lg —lachrymal glands. Myers & Hume, Eur Neuropsychopharmacology, 2002

PET scan safety PET scanning is non-invasive, but it does involve exposure to ionizing radiation. The total dose of radiation is small, however, usually around 7 m. Sv. This can be compared to 2. 2 m. Sv average annual background radiation in the UK, 0. 02 m. Sv for a chest x-ray, up to 8 m. Sv for a CT scan of the chest. An aircrew member is likely to receive a radiation dose of 4 -9 m. Sv per year.