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Research

2D NMR: Heteronuclear Single-Quantum Correlation Spectroscopy (HSQC)

Heteronuclear single-quantum correlation spectroscopy (HSQC) is a 2D NMR technique that reveals one-bond correlations between hydrogen and a heteronucleus. The HSQC experiment is similar to the heteronuclear correlation experiment (HETCOR) but is more sensitive. In the HSQC spectrum, the proton chemical shift is plotted on the horizontal F2 axis, while the 13C chemical shift is plotted on the vertical F1 axis. The corresponding proton and 13C spectra are also shown. The HSQC contour plot does not have any diagonal peaks. All the cross-peaks indicate the protons directly attached to each carbon in a molecule. Similar to the COSY spectrum, imaginary lines are drawn in horizontal and vertical directions to identify the correlated peaks.
For example, the HSQC spectrum of 2-chlorobutane has a carbon signal at 11 ppm that can be assigned to the shielded methyl group and correlated to the proton multiplet at 1.01 ppm. The carbon signal at 24.8 ppm arises from the deshielded methyl group, which correlates to the proton multiplet at 1.52 ppm. Similarly, the methylene carbon signal at 33.3 ppm and methine carbon signal at 60.4 ppm correlate to the multiplets at 1.72 and 3.96 ppm, respectively.&#160; HSQC is a very useful technique for structurally elucidating complex molecules and is routinely used in protein NMR studies.

Heteronuclear single-quantum correlation spectroscopy (HSQC) is a 2D NMR technique that reveals one-bond correlations between hydrogen and a ...

2D NMR: Overview of Heteronuclear Correlation Techniques

Heteronuclear correlation spectroscopy is an analytical technique that investigates the coupling between different types of nuclei, often a proton and an X-nucleus, such as carbon-13 or nitrogen-15. This method is commonly used in nuclear magnetic resonance (NMR) spectroscopy to gain insights into complex chemical compounds&#39; structural and compositional aspects. A typical heteronuclear correlation spectrum displays X-nucleus chemical shifts on one axis and a proton spectrum on the other axis. Cross-peaks reveal the connection between specific protons and X-nuclei.
The main heteronuclear correlation experiments include HETCOR, HSQC, HMQC, and HMBC. HSQC, HMQC, and HMBC record the proton spectrum, whereas the X-nucleus spectrum is recorded by standard heteronuclear correlation spectroscopy or HETCOR. The HETCOR-HMQC-HSQC group of experiments cannot detect X-nuclei without an attached proton. HETCOR is used when ultrahigh peak resolution is required along the X-nucleus axis.
The heteronuclear single quantum correlation technique, or HSQC, investigates proton-to-X-nucleus single bond correlations. In an HSQC experiment, polarization is transferred from a proton nucleus to a neighboring X-nucleus and then back to the proton nucleus. The signal from the proton nuclei is then recorded. HSQC generates a spectrum like that of heteronuclear multiple-quantum correlation spectroscopy or HMQC but uses a different suppression method, providing better X-nucleus resolution along the axis.
Heteronuclear multiple-bond correlation, or HMBC, is a proton-detected experiment, like HMQC but with a longer initial delay time. This experiment is used to observe long-range proton to X-nucleus connectivity separated by 2-3 bonds, with some experiments going out to 4 or 5 bonds. In an HMBC experiment, direct one-bond correlations are suppressed as part of the sequence. The spectra of HMBC give rise to cross peaks that correlate which protons are coupled to what other specific X-nucleus is more than one bond away. The gradient HMBC (gHMBC) pulse sequence offers better suppression of interfering signals, making it particularly useful for analyzing complex molecules with overlapping signals.

Heteronuclear correlation spectroscopy is an analytical technique that investigates the coupling between different types of nuclei, often a proton and an ...

2D NMR: Homonuclear Correlation Spectroscopy (COSY)

Homonuclear correlation spectroscopy, or COSY, is a 2-dimensional NMR technique that provides information about coupled protons. Typically, the geminal and vicinal coupling are observed. For example, consider the COSY spectrum of ethyl acetate, where its 1D proton NMR spectrum is plotted along the vertical and horizontal axes with their corresponding chemical shift scale. Three spots on the diagonal corresponding to the three peaks in the 1D proton spectrum are called diagonal peaks. The COSY spectrum is symmetric about the diagonal, with signals above and below the diagonal called cross-peaks or off-diagonal peaks. An imaginary line is drawn from diagonal peaks parallel to the horizontal axis, leading to a cross peak. A vertical line is then drawn from the same cross peak towards the diagonal peak to correlate the peaks. The off-diagonal peaks correlating the multiplets at 1.25 and 4.2 ppm indicate that the methyl protons are coupled to the methylene protons. The signal at 2 ppm is not associated with cross-peaks because the protons are not involved in homonuclear coupling. A COSY spectrum is useful when overlapping multiplets complicate the corresponding 1D spectrum.

Homonuclear correlation spectroscopy, or COSY, is a 2-dimensional NMR technique that provides information about coupled protons. Typically, the geminal ...

Insensitive Nuclei Enhanced by Polarization Transfer (INEPT)

Insensitive Nuclei Enhanced by Polarization Transfer (INEPT) is an advanced Nuclear Magnetic Resonance (NMR) technique specifically designed to detect and enhance the signals of low-abundance nuclei, such as carbon-13 and nitrogen-15, in small molecules. The fundamental principle behind INEPT is the transfer of polarization from a more abundant and highly polarizable nucleus, typically hydrogen-1, to the low-abundance nucleus of interest. This process effectively boosts the NMR signal of the low-abundance nuclei, making them more easily detectable.
The INEPT technique involves a series of carefully timed radiofrequency (RF) pulses applied to the sample. These RF pulses excite the more abundant nuclei, causing them to align their spins in a specific manner. Through the process of spin coupling, the polarization of the more abundant nuclei is then transferred to the low-abundance nuclei. As a result, the NMR signal of these low-abundance nuclei is significantly enhanced, allowing for a more detailed analysis of the molecular structure.
Various pulse sequences have been developed to improve the observability of these low-abundance nuclei when coupled to a high-receptivity nucleus. The INEPT pulse sequence combines a spin echo and selective population inversion, which includes 90&#176; and 180&#176; pulses on the high-sensitivity (the I spins) and low-sensitivity nuclei (the S spins), respectively. Coupling-constant-based delays between pulses facilitate magnetization transfer through space or bond interactions. Additional RF pulses and delays invert the low-gamma magnetization, producing an observable NMR signal. The net result is an enhanced NMR signal from low-gamma nuclei that would otherwise be challenging to detect.
Various pulse sequences have been developed to improve the detection of low-abundance nuclei when coupled with high-receptivity nuclei such as protons. The INEPT sequence yields enhanced signals for insensitive nuclei, with half of the CH group producing negative peaks and the other half positive peaks. This pattern allows for discrimination between different types of carbon-hydrogen bonds within the molecule.
Decoupling methods can be employed to enhance sensitivity and resolution in distinguishing various carbon-hydrogen bonds, making INEPT an invaluable tool in the chemical and pharmaceutical industries.

Insensitive Nuclei Enhanced by Polarization Transfer (INEPT) is an advanced Nuclear Magnetic Resonance (NMR) technique specifically designed to detect and ...

Two-Dimensional (2D) NMR: Overview

The 1D NMR spectrum of large and complex molecules like natural products has complicated splitting patterns and overlapping signals, which can be easily interpreted using 2-dimensional (2D) NMR. Unlike 1D NMR, 2D NMR has two frequency axes that provide the coupling information between the nucleus A and nucleus B in a molecule. The process from which 2D spectra are obtained has four steps.
The first step is the preparation period, during which nucleus A is excited with a radiofrequency pulse. The second step is the evolution or wait period t1, which is incremented systematically, and no data is observed during this period. The next step is the mixing period, in which a second radiofrequency pulse is introduced, which transfers the magnetization to the spins of nucleus B. In the last step, the magnetization of nuclear spins from B is detected during the acquisition time t2 for each t1. Time domains t1 and t2 are Fourier transformed into frequency domains f1 and f2, and these correspond to two dimensions of 2D spectra, while the third dimension is the intensity. In 2D experiments, coupling between the same kind of nucleus is called homonuclear 2D experiments, whereas coupling between two types of nucleus is called heteronuclear 2D experiments. 2D spectra can be displayed as stacked or contour plots. When presented as stacked plots, 2D spectra are difficult to interpret. The contour plot is the horizontal cross-section of a stacked plot where the size of the circles shows the signal intensity. Its interpretation is straightforward and it is preferred for data analysis.

The 1D NMR spectrum of large and complex molecules like natural products has complicated splitting patterns and overlapping signals, which can be easily ...

2D NMR: Overview of Homonuclear Correlation Techniques

Homonuclear correlation spectroscopy (COSY) is a powerful technique used in Nuclear Magnetic Resonance (NMR) spectroscopy to study the correlations between nuclei of the same type within a molecule. It provides information about scalar couplings between adjacent nuclei, which helps determine connectivity and structural information. There are several COSY variants, each with its unique strengths and experimental parameters.
COSY90 is the standard two-dimensional (2D) COSY experiment that utilizes a second 90-degree pulse to achieve high sensitivity and resolution. It excels in analyzing small to medium-sized molecules and provides information on directly coupled protons. COSY45, similar to COSY90, uses 45-degree pulses instead of 90-degree pulses. This results in reduced sensitivity but improved resolution.
Long-range COSY (LR-COSY) extends the COSY experiment to detect scalar couplings between nuclei further apart in the molecule. It achieves this by combining multiple pulse sequences and magnetization transfers.
Relayed COSY is a variant of COSY that adds extra pulses to the standard pulse sequence to produce cross-peaks between cross-peaks, showing specific molecular connections hidden by overlapping signals.
TOCSY (Total Correlation Spectroscopy), also known as HOHAHA (Homonuclear Hartmann-Hahn Spectroscopy), reveals all through-bond connectivity between all coupled nuclei. TOCSY is especially useful for analyzing molecules with overlapping signals and complex coupling patterns.
NOESY (Nuclear Overhauser Effect Spectroscopy) measures the nuclear overhauser effect, which arises from dipole-dipole interactions between nuclei. It provides information about spatial proximity and can be used to determine the three-dimensional structure of a molecule.
ROESY (Rotating-frame Overhauser Enhancement Spectroscopy) is similar to NOESY but employs a different mechanism to obtain through-space correlations. It provides information about spatial proximity and is particularly useful for studying molecules with weak NOE signals.
In conclusion, choosing a COSY variant depends on the molecule or reaction under investigation and the desired information. The right COSY variant can be determined based on molecular size, coupling complexity, and the need for spatial or long-range connectivity data.

Homonuclear correlation spectroscopy (COSY) is a powerful technique used in Nuclear Magnetic Resonance (NMR) spectroscopy to study the correlations ...

Double Resonance Techniques: Overview

Double resonance techniques in Nuclear Magnetic Resonance (NMR) spectroscopy involve the simultaneous application of two different frequencies or radiofrequency pulses to manipulate and observe two distinct nuclear spins. One important application of double resonance is spin decoupling, which selectively suppresses coupling with one type of nucleus while observing the NMR signal from another nucleus, simplifying the spectrum and enhancing resolution.
Spin decoupling is usually achieved by irradiating the sample atoms with a suitable radio frequency (rf) pulse sequence, effectively eliminating all the coupling with one nuclide. This simplifies the observed spectrum, making it easier to analyze and understand the relationships between different nuclei.
Double resonance experiments can be classified as heteronuclear or homonuclear, depending on whether the two sets of nuclei are of different isotopes or the same isotope, respectively. They can also be selective or nonselective, depending on whether the irradiating frequency covers only a portion or all of the resonance frequencies.
In nonselective heteronuclear decoupling, samples are exposed to an appropriate radiofrequency range to remove all coupling with one nuclide. However, increased external field strengths necessitate more powerful irradiation across broader frequency ranges. In certain instruments, continuous irradiation creates enough heat to cause damage to thermally sensitive samples.
To overcome these problems, modern methods using a series of pulses and exact timing delays, like J-modulated spin echo pulse sequences, can be employed to eliminate or adjust coupling effects within the spectrum.
For example, the attached proton transfer (APT) experiment applies a J-modulated spin echo pulse sequence to focus on the phase of detected carbon signals. Carbon atoms attached to an even number of protons exhibit positive signals in the spectrum, while those bonded to an odd number of protons appear as negative signals.
It utilizes a combination of a 180&#176; proton pulse and broadband decoupling to simplify spectral interpretation and assign multiplicities. The 180&#176; pulse is applied to the protons during the APT experiment. Its role is to refocus the spin coupling evolution that naturally occurs due to interactions between protons and carbons.
Specifically, after the 90&#176; pulse creates transverse magnetization, the 180&#176; pulse ensures that the effects of coupling are frozen during the initial period where the decoupler is turned off. This means the chemical shifts evolve only during the time 1/J&#8203; (the coupling constant period) after the first 180&#176; pulse.
By carefully timing this pulse sequence, the experiment isolates carbon multiplicities by utilizing the J-coupling between carbons and their attached protons. After the coupling evolution period (1/J&#8203;), broadband decoupling is turned on. This removes the J-coupling signals, collapsing multiplets into single peaks for each carbon resonance.
The decoupling ensures that carbon signals are free of splitting, allowing for a clear differentiation of signals based on phase (positive or negative) rather than splitting patterns.
The APT technique selectively enhances carbon signals, providing valuable information about carbon-proton connectivity, the number of attached hydrogen atoms, and the overall molecular structure.

Double resonance techniques in Nuclear Magnetic Resonance (NMR) spectroscopy involve the simultaneous application of two different frequencies or ...

&sup1;H NMR of Labile Protons:  Deuterium (&sup2;H) Substitution

This lesson illustrates the role of deuterium substitution in simplifying the NMR spectrum of compounds comprising labile protons. One method employed is the use of deuterium. Amongst the three isotopes of hydrogen, deuterium (2H) has a nucleus composed of one proton and one neutron. When the D2O solvent is added to a pure dry ethanol solution, its labile proton is substituted with deuterium.
<img alt="Figure1" src="/files/ftp_upload/12280/12280-PT_Figure_1.svg" style="text-align: center; height: 700px;" />
Figure 1. The comparison of the proton NMR spectra of pure dry ethanol and the same in D2O solvent.
The signals from deuterium are not observed in a proton NMR spectrum, as deuterium&#8211;proton coupling is negligible, and no spin-spin splitting occurs between them. As shown in Figure 1, the NMR spectra of pure ethanol and ethanol in deuterium, the disappearance of the triplet in the latter, confirms that it corresponds to the labile &#8211;OH proton. Furthermore, the methylene protons that initially showed up as a multiplet transform to a quartet, proving that the multiplet is due to the coupling with the &#8211;OH proton and the methyl protons.

This lesson illustrates the role of deuterium substitution in simplifying the NMR spectrum of compounds comprising labile protons. One method employed is ...

Nuclear Overhauser Enhancement (NOE)

Irradiation of a spin-active nucleus causes an increase or decrease in the signal intensity of neighboring nuclei that are not necessarily chemically bonded or involved in J-coupling. &#160;This phenomenon, called the Nuclear Overhauser Enhancement (NOE), results from through-space interactions between the nuclear spins. The NOE effect decreases with increasing internuclear distance and is generally not observed beyond 4 angstroms. In NOE, dipole-dipole interactions between neighboring spin-active nuclei result in the transfer of nuclear spin polarization. These interactions can cause an increase or decrease in the signal intensity, which results in a positive or negative NOE, respectively.
NOE can be applied to improve the signal intensity of less sensitive nuclei such as carbon-13. Proton-decoupled carbon-13 spectra show a positive NOE effect, where the carbon signal intensities are substantially increased compared to those in proton-coupled spectra.
Targeted irradiation of specific nuclei can also reveal through-space proximity, which helps confirm stereochemistry and verify spectral peak assignments. The NOE effect is also applied in 2D NMR experiments, such as Nuclear Overhauser Effect Spectroscopy (NOESY), to determine the 3D structure of proteins.

Irradiation of a spin-active nucleus causes an increase or decrease in the signal intensity of neighboring nuclei that are not necessarily chemically ...

&sup1;H NMR of Labile Protons: Temporal Resolution

Protons bonded to heteroatoms such as nitrogen and oxygen exhibit a range of chemical shift values. This is due to the varying degree of hydrogen bonding between the proton and the heteroatom in other molecules. The extent of hydrogen bonding affects the electron density around the proton, thereby giving different chemical shift values for the protons in the proton NMR spectrum.
The &#8211;OH proton in alcohols typically appears in the range of &#948; 2 to 5 ppm but can vary depending on the specific alcohol and conditions. This &#8211;OH proton undergoes rapid proton exchange with other molecules and is referred to as a labile proton. So, the exact &#948; value of the &#8211;OH proton and the spin-spin coupling involving the &#8211;OH proton and the other protons in the alcohol depends on the rate of the &#8211;OH proton exchange. The proton exchange rate, in turn, depends on multiple factors, including the purity of the alcohol sample, temperature, and solvent.
<img alt="Figure1" src="/files/ftp_upload/12279/12279-PT_Figure_1.svg" style="text-align: center; height: 350px;" />
Figure 1. The triplet of a &#8211;OH proton in the proton NMR spectrum of neat ethanol.
For example, the &#8211;OH proton exchange in a pure dry ethanol sample is very slow on the NMR time scale, giving enough time for the spin-spin coupling. Consequently, as depicted in Figure 1, the proton NMR spectrum of pure dry ethanol shows a triplet for the &#8211;OH proton due to the spin-spin coupling with adjacent methylene protons. The methylene protons are seen as a multiplet due to the coupling with the &#8211;OH proton and the methyl protons.
The presence of trace amounts of an acid or base increases the proton exchange rate. The proton exchange becomes rapid, and the NMR spectrometer only records an average of all the possible environments for the &#8211;OH proton.
<img alt="Figure2" src="/files/ftp_upload/12279/12279-PT_Figure_2.svg" style="text-align: center; height: 325px;" />
Figure 2. The broad singlet of a &#8211;OH proton in the proton NMR spectrum of neat ethanol.
As a result, as recorded in Figure 2, the &#8211;OH proton exhibits a broad singlet. The protons from the adjacent methylene group present a quartet where the splitting is caused only by the adjoining methyl group.

Protons bonded to heteroatoms such as nitrogen and oxygen exhibit a range of chemical shift values. This is due to the varying degree of hydrogen bonding ...

&sup1;H NMR of Conformationally Flexible Molecules: Variable-Temperature NMR

The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one proton, the remaining eleven protons are replaced by deuterium. The deuterium substitution avoids the possible peak splitting caused by the spin-spin coupling between the adjacent protons. The remaining proton flips between the axial and equatorial positions.
<img alt="Figure1" src="/files/ftp_upload/13016/13016-PT_Figure_1.svg" style="text-align: center; height: 480px;" />
Figure 1. The temperature-dependent proton NMR spectra of cyclohexane.
Figure 1 depicts the proton NMR spectrum of the deuterium substituted sample, recorded at various temperatures. At room temperature, the rapid ring flipping of cyclohexane results in a single sharp peak. As the temperature is lowered to &#8722;60&#176;C, the rate of chair-chair interconversion reduces, resulting in the broadening of the peak.
Further lowering of the temperature broadens the peak, forming a saddle that splits into two peaks. On reaching a temperature lower than &#8722;89&#176;C, two sharp, well-resolved peaks corresponding to the equatorial and axial protons are formed. The peaks corresponding to the equatorial and axial protons occur at &#948; 1.62 and 1.14, respectively. At such low temperatures, the rate of chair-chair interconversion is reduced significantly, enabling the detection of the two distinct sets of protons on the NMR time scale.

The axial and equatorial protons in cyclohexane can be distinguished by performing a variable-temperature NMR experiment. In this process, except for one ...

&sup1;H NMR of Conformationally Flexible Molecules: Temporal Resolution

At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately 105 times per second. These two chair conformers are in equilibrium. The rapid ring flipping results in the interconversion of the axial proton to an equatorial proton and an equatorial to the axial proton. Such interconversions are too rapid and cannot be detected on the NMR timescale. Hence, the NMR spectrometer cannot distinguish between the axial and equatorial protons, resulting in a single peak at &#948; 1.4.
Similarly, NMR averages all the conformations of any molecule with rapid conformational equilibria. For example, the CH3 protons in bromoethane have a single resonance and coupling constant for splitting by the CH2 protons due to the rapid internal rotation of the carbon-carbon bond. Lastly, besides conformational equilibria, the time-averaging effect of NMR spectroscopy is also observed in some chemical reactions.

At room temperature, the chair conformer of cyclohexane undergoes rapid ring flipping between two equivalent chair conformers at a rate of approximately ...

Mass Spectrometry: Carboxylic Acid, Ester, and Amide Fragmentation

The fragmentation patterns observed for compounds such as carboxylic acids, esters, and amides in the mass spectra include &#9082;-cleavage and McLafferty rearrangement. Fragmentation by &#9082;-cleavage preferentially occurs at the carbon-carbon bond at the &#9082;-position next to the carboxylic group to generate a neutral radical and a cation. Long chain compounds with hydrogen at their &#947;-carbon undergo McLafferty rearrangement to give a radical cation and a neutral alkene.
For example, the fragmentation of butyramide is demonstrated in Figure 1. The molecular ion peak of butyramide, which contains one nitrogen atom, shows an odd mass-to-charge ratio of 87. Fragmentation of butyramide molecular ion by &#9082;-cleavage produces a cation at a mass-to-charge ratio 44. In addition to &#9082;-cleavage, butyramide molecular ion also undergoes fragmentation via McLafferty rearrangement. The base peak at the mass-to-charge ratio 59 arises due to McLafferty rearrangement.
<img alt="Figure1" src="/files/ftp_upload/13051/13051_PT_Figure_1.svg" style="text-align: center; height: 250px;" />

The fragmentation patterns observed for compounds such as carboxylic acids, esters, and amides in the mass spectra include &#9082;-cleavage and McLafferty ...

Chemical Ionization (CI) Mass Spectrometry

The molecular ion peak of a molecule in the mass spectrum provides vital information for molecular identification. However, conventional electron impact ionization can lead to the rapid dissociation of some molecular ions before they reach the detector. A milder ionization method is required to increase the lifetime of such ionized analyte molecules. Chemical ionization (CI) is a gas-phase protonation reaction useful for mass-analyzing analyte molecules that are easily protonated to yield the corresponding conjugate acid. In this process, the sample is mixed with an excess reagent gas, which ensures the electron impact occurs primarily on the reagent gas. The charged species formed from the reagent protonates the analyte molecule, producing a relatively stable protonated analyte (conjugate acid) compared to the molecular ion. This results in an M+1 peak in the mass spectrum. The conjugate acid may then undergo fragmentation that generates additional signals.
For example, the CI of di-sec-butyl ether in methane gas illustrates this process. When the ether is mixed with excess methane gas as a reagent, electron impact occurs on methane rather than the ether. The resulting methane radical cation can react with another methane molecule to generate a methane radical and a methanium ion. The methanium ion is a source of gas-phase protons, which can protonate the ether to form its conjugate acid. The sequential reactions during the chemical ionization of di-sec-butyl ether are depicted in Figure 1.
<img alt="Figure1" src="/files/ftp_upload/12300/12300_PT_Figure_1.svg" style="text-align: center; height: 175px;" />
Figure 1: Chemical ionization of di-sec-butyl ether methane mixture.
This conjugate acid of the ether (m/z = 131) is relatively more stable than the molecular ion (m/z = 130) of ether formed via the conventional electron impact ionization. In the traditional route, the molecular ion undergoes fragmentation via &#945; cleavage, giving a signal at m/z = 101. Figure 2 illustrates the reactions that occur during electron impact ionization directly on di-sec-butyl ether.
<img alt="Figure2" src="/files/ftp_upload/12300/12300_PT_Figure_2.svg" style="text-align: center; height: 175px;" />
Figure 2: Electron impact ionization of di-sec-butyl ether and fragmentation of the molecular ion.
So, the mass spectra of di-sec-butyl ether ionized via CI feature an M+1 peak at m/z = 131. On the other hand, mass spectra of di-sec-butyl ether ionized via electron impact ionization do not show any peak at the m/z value of its molecular weight. Figures 3a and 3b show the mass spectra of di-sec-butyl ether ionized via the electron impact and chemical ionization methods, respectively.
<img alt="Figure3" src="/files/ftp_upload/12300/12300_PT_Figure_3.svg" style="text-align: center; height: 225px;" />
Figure 3:&#160;a) No m/z = 130 peak is visible in the mass spectrum obtained via electron impact ionization of di-sec-butyl ether. b) The m/z = 131 peak is clearly visible in the mass spectrum obtained via chemical ionization of di-sec-butyl ether.

The molecular ion peak of a molecule in the mass spectrum provides vital information for molecular identification. However, conventional electron impact ...

Mass Spectrometry: Alkyl Halide Fragmentation

Chlorine isotopes exist as 35Cl and 37Cl in a 3:1 ratio, while bromine isotopes exist as 79Br and 81Br in a 1:1 ratio. The mass spectrum of alkyl halides typically produces two distinct molecular ion peaks, the molecular ion peak, [M], and the molecular ion plus two, [M + 2] peak. The relative heights of these two peaks are proportional to the isotopic abundance ratios of the halide. For example, 2&#8208;chloropropane and 1&#8208;bromopropane display two peaks with relative peak heights in a 3:1 and 1:1 ratio, respectively.
Alkyl halides typically lose a non-bonding electron from the halogen to form molecular ions. The base peak results from the heterolytic cleavage of the carbon&#8211;halogen bond, where the bonding electrons go to the most electronegative atom, forming a cation and halogen atom. Interestingly, the &#9082;-cleavage is observed only in alkyl chlorides, not alkyl bromides. In alkyl chlorides, the&#160; C&#8211;Cl and C&#8211;C bonds exhibit similar strengths, while in alkyl bromides, the C&#8211;Br bond is weaker than the C&#8211;C bond. Consequently, the alkyl chlorides form a stable cation, where the positive charge is shared between the two atoms.
While less commonly discussed, fluoroalkanes and iodoalkanes exhibit unique fragmentation behavior. Fluoroalkanes, due to the strength of the C&#8211;F bond and the presence of only one isotope (19F), show limited fragmentation and lack isotopic peaks. Iodoalkanes, with their weak C&#8211;I bond and a single isotope (127I), predominantly fragment by losing iodine, resulting in simpler spectra with less isotopic splitting.

Chlorine isotopes exist as 35Cl and 37Cl in a 3:1 ratio, while bromine isotopes exist as 79Br and 81Br in a 1:1 ratio. The mass spectrum of alkyl halides ...

Electrospray Ionization (ESI) Mass Spectrometry

Higher molecular weight biomolecules are nonvolatile compounds that may decompose before ionizing or vaporizing during mass analysis with conventional electron impact ionization methods. Accordingly, electrospray ionization (ESI) is the favored method for vaporizing and ionizing biomolecules as it circumvents rapid fragmentation and enables the recording of mass signals for the entire biomolecule.
ESI utilizes electrical energy to transfer ions from the liquid phase of the sample into the gaseous phase. The analyte biomolecule is premixed with an ionic liquid&#8212;a nonmolecular compound serving as the ionization source. The solution is sprayed through a high-voltage capillary to generate a fine aerosol. The voltage difference applied between the capillary and the entrance of the analysis chamber causes the movement of charged droplets toward the analysis chamber. The ionic liquid from the aerosol evaporates during this movement, leaving behind a variably protonated or ionized analyte molecule. These charged species are detected in the mass spectrum at an m/z value equivalent to the sum of the analyte molecule&#39;s molecular mass and the ions&#39; molecular weight from the ionic liquid associated with the analyte molecule.
The position of mass signals varies depending on the type of cations present in the ionic liquid. For example, the presence of sodium ions in the ionic liquid leads to an (M+23) peak in the mass spectra, while the presence of a proton results in an (M+1) peak.

Higher molecular weight biomolecules are nonvolatile compounds that may decompose before ionizing or vaporizing during mass analysis with conventional ...

Matrix-Assisted Laser Desorption Ionization (MALDI)

Matrix-assisted laser desorption ionization (MALDI) is a powerful analytical technique used in mass spectrometry. It enables the identification and characterization of various biomolecules, including proteins, peptides, nucleic acids, and carbohydrates. MALDI spectrometry is widely employed in biological and medical research, as well as in fields like pharmacology and biochemistry.
The analyte of interest, a biomolecule or a mixture of biomolecules, is mixed with a suitable matrix material. The matrix is usually an organic compound, such as a small organic acid or a crystalline substance, that facilitates ionization. This analyte-matrix mixture is then deposited onto a target surface, inserted into the mass spectrometer, and dried. During drying, the matrix forms small crystals that incorporate the analyte molecules within their structure.
Once the sample is prepared, a pulsed laser is directed onto the target surface. The matrix molecules absorb the laser beam energy, causing them to heat up and vaporize rapidly. This process is known as laser desorption. As the matrix molecules vaporize, they carry the embedded analyte molecules. The vaporized analyte molecules become ionized through a process called proton transfer. The proton transfer occurs between the matrix and the analyte molecule. The matrix molecule donates a proton to the analyte molecule, resulting in the formation of protonated ions. The analyte ions are then accelerated by an electric field and further separated based on their mass-to-charge ratio in a time-of-flight mass analyzer.
The mass spectrum obtained from MALDI spectrometry provides valuable information about the mass and relative abundance of the analyzed biomolecules.

Matrix-assisted laser desorption ionization (MALDI) is a powerful analytical technique used in mass spectrometry. It enables the identification and ...

Mass Spectrometry: Aldehyde and Ketone Fragmentation

In mass spectrometry, the fragmentation of aliphatic aldehydes and ketones generally occurs through three key mechanisms: &#945;-cleavage, inductive cleavage, and the McLafferty rearrangement.
<ol>
	<li>&#945;-Cleavage 
	&#945;-Cleavage is a common fragmentation in carbonyl compounds where the bond adjacent to the carbonyl group is broken. This process produces an alkyl radical and an acylium cation, which is often detected in the mass spectrum due to its stability.</li>
	<li>Inductive Cleavage 
	In inductive cleavage, fragmentation yields an acyl radical and an alkyl cation. This occurs when electrons are drawn toward the carbonyl, weakening adjacent bonds and resulting in a distinctive fragmentation pattern. For example, in the mass spectrum of 5-methyl-2-hexanone, inductive cleavage produces an alkyl cation at a mass-to-charge (m/z) ratio of 71.</li>
	<li>McLafferty Rearrangement 
	The McLafferty rearrangement is a specific fragmentation pattern for carbonyl compounds with &#947;-hydrogen (hydrogen on the third carbon from the carbonyl group). The molecule undergoes a six-membered cyclic transition in this rearrangement, yielding a radical cation and a neutral alkene. For 5-methyl-2-hexanone, this rearrangement results in a peak at m/z 58.</li>
</ol>
Example: Fragmentation of 5-methyl-2-hexanone 
In the mass spectrum of 5-methyl-2-hexanone, the molecular ion undergoes these fragmentation patterns:
<ol style="list-style-type: circle;">
	<li>Inductive cleavage produces an alkyl cation at m/z 71.</li>
	<li>&#945;-Cleavage results in the base peak at m/z 43.</li>
	<li>McLafferty rearrangement creates a distinct peak at m/z 58.</li>
</ol>
An additional diagnostic feature in aldehydes is the M&#8722;1 peak, which arises due to the &#945;-cleavage of the aldehyde proton. In mass spectrometric analysis, this peak can help identify aldehydes, specifically among other carbonyl compounds.
Understanding these fragmentation pathways is crucial for interpreting mass spectra, particularly in identifying functional groups and distinguishing between similar compounds.

In mass spectrometry, the fragmentation of aliphatic aldehydes and ketones generally occurs through three key mechanisms: &#945;-cleavage, inductive ...

Mass Spectrometry: Alcohol Fragmentation

Alcohols (R-OH) ionize to lose one non-bonded electron from the oxygen atom, forming molecular ions. Due to their tendency to fragment rapidly, the intensity of the molecular ion peak in the mass spectrum is weak or sometimes absent. The fragmentation patterns for alcohols occur in two ways, i.e. &#9082;-cleavage and dehydration. During &#9082;-cleavage, the bond at the &#9082;-position adjacent to the hydroxyl group cleaves to give a resonance-stabilized cation and a radical. However, intramolecular dehydration involves losing a water molecule from an alcohol, forming an alkene cation, which shows a peak at M&#8722;18. Consider the fragmentation of butanol as shown below. &#9082;-cleavage produces a base peak at a mass-to-charge ratio of 31. In the case of dehydration, the fragmentation forms an alkene radical cation at a mass-to-charge ratio of 56.
<img alt="Figure1" src="/files/ftp_upload/13046/13046-PT_Figure_1.svg" style="text-align: center; height: 175px;" />

Alcohols (R-OH) ionize to lose one non-bonded electron from the oxygen atom, forming molecular ions. Due to their tendency to fragment rapidly, the ...

Mass Spectrometry: Alkyne Fragmentation

The fragmentation of alkynes preferentially occurs at the carbon&#8211;carbon bond between the &#945; and &#946; carbon of the alkyne bond to generate a 3-propynyl cation (or propargyl cation). In terminal alkynes, there is the only type of fragmentation that yields the 3-propynyl cation. The unsubstituted 3-propynyl cation exhibits a peak at a mass-to-charge ratio of 39. In internal alkynes, the 3-propynyl cation is substituted. For example, 2-pentyne fragments into methyl-substituted 3-propynyl cation, which subsequently features as a mass signal at the mass-to-charge ratio of 56. The 3-propynyl cation is resonance-stabilized, and the corresponding mass signal is intense in the mass spectrum of alkynes. Figure 1 shows the fragmentation of 1-pentyne into an ethyl radical and a resonance stabilized 3-propynyl cation.
<img alt="Figure1" src="/files/ftp_upload/13045/13045-PT_Figure_1.svg" style="text-align: center; height: 115px;" />
Figure 1: Fragmentation of 1-pentyne molecular ion to yield the 3-propynyl cation.
Another fragmentation pathway observed in terminal alkynes is the loss of hydrogen from the terminal sp carbon. This results in a mass signal with a mass-to-charge ratio of one unit less than the molecular ion. This M&#8211;1 peak is very intense and becomes the base peak in the mass spectra of many alkynes, so it can be used to identify alkynes.
<img alt="Figure2" src="/files/ftp_upload/13045/13045-PT_Figure_2.svg" style="text-align: center; height: 275px;" />
Figure 2: The mass spectrum of 1-pentyne.

The fragmentation of alkynes preferentially occurs at the carbon&#8211;carbon bond between the &#945; and &#946; carbon of the alkyne bond to generate a ...

Mass Spectrometry: Aromatic Compound Fragmentation

Upon ionization, aromatic compounds generate a molecular ion that is observed as a prominent peak in their mass spectra. For example, the molecular ion peak for benzene appears at a mass-to-charge ratio of 78, while toluene is observed at a mass-to-charge ratio of 92. The molecular ion benzene is highly stable and does not readily undergo further fragmentation due to the significant amount of energy required to disrupt the aromatic stability of the benzene ring. In contrast, the molecular ion of alkyl&#8208;substituted benzenes, such as toluene, can undergo fragmentation by losing a hydrogen atom, forming a benzylic carbocation. This carbocation can rearrange to form the resonance-stabilized tropylium cation, which appears in the mass spectra as a strong peak. In the case of toluene, this strong peak is observed at a mass-to-charge ratio of 91.

Upon ionization, aromatic compounds generate a molecular ion that is observed as a prominent peak in their mass spectra. For example, the molecular ion ...

Mass Spectrometry: Cycloalkene Fragmentation

The molecular ions of cycloalkenes undergo fragmentation via a retro-Diels&#8211;Alder reaction.

The reaction proceeds via the cleavage of two carbon-carbon bonds in the cycloalkene to yield ethene. The remaining part of the cycloalkene structure is a dienyl radical cation with a molecular weight of 28 u lower than the molecular ion. This fragmentation pathway is similar to the fragmentation of cycloalkanes releasing ethene, differing only in the resultant radical cation. An alkyl species forms from the cycloalkane, whereas a dienyl species originates from the cycloalkene.

Retro-Diels&#8211;Alder reactions of cycloalkenes are also similar to the McLafferty-rearrangement-type fragmentation observed in acyclic alkenes with hydrogen on the &#947; carbon. In both cases, cleavage occurs at two positions, yielding an ethene molecule and an alkenyl species. In acyclic alkenes, the cleavage occurs at one carbon-carbon bond and a carbon-hydrogen bond, along with rearranging hydrogen from one carbon to another. In cyclic alkenes, cleavage occurs at two carbon&#8211;carbon bonds without any atomic rearrangement. Figure 1 depicts the fragmentation of cyclohexene via a retro-Diels&#8211;Alder reaction.
<img alt="Figure1" src="/files/ftp_upload/13044/13044-PT_Figure_1.svg" style="text-align: center; height: 90px;" />
Figure 1: Fragmentation of cyclohexene via a retro-Diels&#8211;Alder reaction.
In addition to the retro-Diels&#8211;Alder reaction, branched cycloalkenes exhibit fragmentation via cleavage of the side chain to form a cycloalkene cation. For example, the fragmentation of 1-methyl-1-cyclohexene via a retro-Diels&#8211;Alder reaction and side-chain cleavage are shown in Figure 2.
<img alt="Figure2" src="/files/ftp_upload/13044/13044-PT_Figure_2.svg" style="text-align: center; height: 225px;" />
Figure 2: Fragmentation of 1-methyl-1-cyclohexene via (top) a retro-Diels&#8211;Alder reaction; (bottom) side-chain cleavage.
The corresponding signals of the isoprenyl radical cation and the cyclohexenyl cation are evident in the mass spectrum of 1-methyl-1-cyclohexene shown in Figure 3.
<img alt="Figure3" src="/files/ftp_upload/13044/13044-PT_Figure_3.svg" style="text-align: center; height: 250px;" />
Figure 3: Mass spectrum of 1-methyl-1-cyclohexene.

The molecular ions of cycloalkenes undergo fragmentation via a retro-Diels&#8211;Alder reaction.

The reaction proceeds via the cleavage of two ...

Mass Spectrometry: Amine Fragmentation

Amines can be identified using mass spectroscopy based on their characteristic fragmentation patterns. The molecular ions of amines undergo fragmentation via &#9082;-cleavage. The &#9082;-cleavage of the carbon-carbon bonds in amines generates an alkyl radical and resonance-stabilized nitrogen-containing cation.
In amines, the number of nitrogen atoms affects the mass of the molecular ion, which is described by the nitrogen rule of mass spectrometry. This rule states that a compound containing a single or an odd number of nitrogen atoms produces a molecular ion with an odd molecular weight, while a compound with no or an even number of nitrogen atoms generates a molecular ion with an even molecular weight.
For example, the mass spectrum of 3-methyl-1-butanamine, which contains one nitrogen atom, displays a molecular ion having an odd mass-to-charge ratio of 87. Fragmentation of this molecular ion via &#9082;-cleavage produces a base peak, which features a mass signal at a mass-to-charge ratio of 30, corresponding with the loss of the 2-methyl propyl radical.
Similarly, the fragmentation of triethylamine via &#9082;-cleavage generates a cation at a mass-to-charge ratio of 86. The molecular ion peak shows an odd mass-to-charge ratio of 101, as shown below.
<img alt="Figure1" src="/files/ftp_upload/13048/13048_PT_Figure_1.svg" style="text-align: center; height: 105px;" />

Amines can be identified using mass spectroscopy based on their characteristic fragmentation patterns. The molecular ions of amines undergo fragmentation ...

Mass Spectrometry: Long-Chain Alkane Fragmentation

The molecular ions of linear alkanes prefer to fragment at the carbon-carbon bond away from the end of the chain since the cleavage of an inner bond creates a stable carbocation and a stable radical. Consequently, the mass signals of linear alkanes feature intense peaks in the middle of the mass-to-charge ratio plot with weaker peaks on either end. The fragmentation of each carbon-carbon bond with the release of a methyl group in each splitting leads to prominent peaks in the mass spectra separated by 14 u. Smaller mass signals near each prominent peak result arise from secondary fragmentation at the carbon-hydrogen bond.
For example, consider the fragmentation pattern of n-hexane shown in Figure 1 and the corresponding mass spectra in Figure 2.
<img alt="Figure1" src="/files/ftp_upload/12299/12299-PT_Figure_1.svg" style="text-align: center; height: 500px;" />
Figure 1: Fragmentation of n-hexane molecular ion.
<img alt="Figure2" src="/files/ftp_upload/12299/12299-PT_Figure_2.svg" style="text-align: center; height: 275px;" />
Figure 2: Mass spectrum of n-hexane.
The signals at a mass-to-charge ratio of 71, 57, 43, 29, and 15 indicate that the cleavage can occur at all carbon-carbon bonds in the molecule. However, the relative abundance of these peaks varies. The difference between molecular ion signal and signal at 71 indicates the separation of methyl groups (M.W. = 15 u) group from molecular ions. Further release of a CH2 group from that fragment (M.W. = 14 u) results in a signal at 57. The signals at 43, 29, and 15 are due to the subsequent releases of CH2 groups. The abundance of signals at 15 and 71 is minimal due to the least probability for the formation of unstable methyl carbocation or a methyl radical, respectively. The base peak at 43 indicates the most preferred fragmentation, which yields a pair of stable carbocation and radical.

The molecular ions of linear alkanes prefer to fragment at the carbon-carbon bond away from the end of the chain since the cleavage of an inner bond ...

The Split Brain

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
The study of how damage to the brain affects cognitive functioning has historically been one of the most important tools for cognitive neuroscience. While the brain is one of the most well protected parts of the body, there are many events that can affect the functioning of the brain. Vascular issues, tumors, degenerative diseases, infections, blunt force traumas, and neurosurgery are just some of the underlying causes of brain damage, all of which may produce different patterns of tissue damage that affect brain functioning in different ways.
The history of neuropsychology is marked by several well-known cases that led to advances in the understanding of the brain. For instance, in 1861 Paul Broca observed how damage to the left frontal lobe resulted in aphasia, an acquired language disorder. As another example, a great deal about memory has been learned from patients with amnesia, such as the famous case of Henry Molaison, known for many years in the neuropsychology literature as &#34;H.M.,&#34; whose temporal lobe surgery led to a profound deficit in forming certain kinds of new memories.
While the observation and testing of patients with focal brain damage has provided neuroscience with insight into the functioning of the brain, great care must be taken in designing tests to reveal the specific nature of the deficit. Also, because the brain is a complex network of interconnected neurons, damage to one brain region can affect functioning in regions far away from the damage. To demonstrate how brain damage can affect connections among brain regions, this video examines the case of the so-called split brain.
The corpus callosum is a large bundle of fibers that connects the left and right hemispheres of the brain. It is one of the largest white matter tracts in the brain and can be easily recognized on a sagittal view of the midline of the brain. In the 1960s, neurosurgeons discovered that cutting the corpus callosum could be a successful treatment for certain kinds of epilepsy, which involves uncontrollable neural activity spreading through the brain. People who underwent the split-brain operation had their two hemispheres surgically separated, such that the left and right hemispheres were no longer able to communicate. This condition allowed experimenters to probe the functions of the left and right hemisphere independently, to learn about the relative abilities, and about the nature of communication between them.
This video demonstrates how to test a split-brain patient to reveal some of the differences between the two hemispheres of the brain and to see some dramatic consequences of such a disconnection. The original versions of these experiments were developed by Michael Gazzaniga and colleagues1, 2 and later were elaborated upon by others;3 the version presented here incorporates more recent modernizations of the methodology.

Testing Cognitive Abilities in Split-brain Patients Using Visual Stimuli

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
The study of how damage to the brain affects cognitive ...

Motor Maps

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
One principle of brain organization is the topographic mapping of information. Especially in sensory and motor cortices, adjacent regions of the brain tend to represent information from adjacent parts of the body, resulting in maps of the body expressed on the surface of the brain. The primary sensory and motor maps in the brain surround a prominent sulcus known as the central sulcus. The cortex anterior to the central sulcus is known as the precentral gyrus and contains the primary motor cortex, while the cortex posterior to the central sulcus is known as the postcentral gyrus and contains the primary sensory cortex (Figure 1).
<img alt="Figure 1" src="/files/ftp_upload/10175/10175fig1.jpg" /> 
Figure 1: Sensory and motor maps around the central sulcus. The primary motor cortex, which contains a motor map of the body&#39;s effectors, is anterior to the central sulcus, in the precentral gyrus of the frontal lobe. The primary somesthetic (sensory) cortex, which receives touch, pain, and temperature information from the external parts of the body, is located posterior to the central sulcus, in the postcentral gyrus of the parietal lobe.
In this experiment, functional neuroimaging is used to demonstrate the motor map in the precentral gyrus. This map is often called the motor homunculus, which is Latin for &#34;little man,&#34; because it is as if there is a little version of one&#39;s self represented in this part of a person&#39;s brain. One interesting property of this map is that more cortical space is devoted to body parts requiring finer control, such as the hands and mouth, which results in disproportionate representation of those appendages in the cortex. Also, because of the anatomy of the motor system, the neurons that control the right side of the body are in the left primary motor cortex, and vice versa. Therefore, when a participant in the experiment is asked to move their right hand or foot, an increased activation on their left precentral gyrus is expected.
In this experiment, participants are asked to alternately move their hands and feet, on the left and right sides, while their brain activity is measured with fMRI. Since the fMRI signal relies on changes in blood oxygenation, which are slow in comparison to the movements the participants make, the periods of movement are separated with periods of stillness to ensure that the various conditions can be distinguished from each other and from the resting baseline. To achieve precise timing of the movements, participants are instructed on when to begin and end each movement with a visual cue. The methods in this video are similar to those used by several fMRI studies that have demonstrated somatotopy in primary motor cortex.1,2

Studying Brain Activation and Motor Maps Using fMRI

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
One principle of brain organization is the topographic ...

Perspectives on Neuropsychology

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212; University of Southern California
Neuropsychology is a complex field, as it investigates how mental processes are executed in the brain&#8212;events that integrate concepts from biochemistry, biology, psychology, and neuroscience. Although the multidisciplinary nature of neuropsychology prepares young learners for a variety of careers, it also poses a challenge in that it forces students to study concepts outside of their comfort zone. For example, a psychology major may have difficulty grasping neuroanatomy&#8212;a challenging topic in itself&#8212;given that the brain is a complicated, three-dimensional organ that is typically represented two-dimensionally in textbooks.
This JoVE collection in Neuropsychology introduces major concepts and methods in the field, and showcases how advances in imaging technology have allowed us to look inside the brain and visualize its structure and function. Importantly, these videos are also meant to reassure students that you don&#8217;t need to be an expert in all aspects of neuropsychology to understand how the brain shapes our experiences, behaviors, and social interactions in everyday life. For instance, the video "Decision-making and the Iowa Gambling Task" explores how damage to a specific region of the brain can affect an individual&#8217;s proclivity for risky decisions, like stealing.
These JoVE videos in Neuropsychology provide the perfect introduction to this complex topic, and also explore some of the potential, exciting future directions in this field. With further advances in technology, one day researchers might even be able to visualize dynamic changes in a person&#8217;s brain outside of a laboratory setting&#8212;for example, when they are sitting in a classroom listening to a lecture on neuropsychology.

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212; University of Southern California
Neuropsychology is a complex field, as it ...

Decision-making and the Iowa Gambling Task

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Decision-making is an important component of human executive function, in which a choice about a course of action or cognition is made from many possibilities. Damage to the inferior parts of the frontal lobes can affect a person's ability to make good decisions. However, while decision-making deficits can have a large impact on one's life, these deficits can be difficult to quantify in the laboratory. In the mid-1990s, a task was designed to mimic real life decision-making in the laboratory. This task, known as the Iowa Gambling Task (IGT), is a cognitively complex task used widely in research and clinical studies as a highly sensitive measure of decision-making ability.1-3
In the IGT, a participant is shown four decks of cards and chooses to reveal a card from one deck on each turn. When a card is turned over, the participant will receive some money, but sometimes will also be required to pay a penalty. Two of the decks have higher payoffs, but also have high penalties such that choosing from these decks leads to a net loss in the long term. The other two decks have lower payoffs, but also present smaller penalties, so that choosing from these decks leads to a net gain. Thus, to make an advantageous choice, participants must integrate information about losses and gains over time.
This video demonstrates how to administer the IGT to compare the performance of patients with damage to the ventromedial prefrontal cortex to a group of matched control subjects, revealing the unique contribution of this brain region to decision-making.

Decision-making and the Iowa Gambling Task- Effect of VMPFC Damage

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Decision-making is an important component of human ...

Executive Function in Autism Spectrum Disorder

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Attention, working-memory, planning, impulse control, inhibition, and mental flexibility are important components of human cognition that are often referred to as executive functions. Autism spectrum disorder is a developmental disorder that is characterized by impairments in social interaction, communication, and repetitive behaviors. It is a disorder that lasts a lifetime, and is thought to affect 0.6% of the population. The symptoms of autism suggest a deficit in executive function, which may be assessed by specialized neuropsychological tests. By employing several tests that each emphasize different aspects of executive function, we can gain a more complete picture of the cognitive profile of the disorder. 
One such task, known as the Wisconsin Card Sorting Test (WCST), is a cognitively complex task used widely in research and clinical studies as a highly sensitive measure of deficits in executive function. It tests a person's ability to shift attention and tests their flexibility with changing rules and reinforcement.1 In the WCST, a participant is presented with four stimulus cards, incorporating three stimulus parameters: color, shape, and number. The participant is asked to sort response cards according to different principles, changing their sorting criteria based on feedback from the experimenter. Participants try out different rules until they find the correct method for sorting the cards. Patients with executive dysfunction tend to get stuck in the card sorting task, unable to change their sorting strategy. This persistence with an incorrect strategy is called perseveration. 
A second task, The Tower of London (ToL) is a test dependent on complex planning, re-evaluation, and updating of planned moves. Individuals with autism have been reported to be impaired on tasks involving planning.2 In the ToL task, individuals must move disks from a prearranged sequence on three pegs to match a goal state in as few moves as possible, following specific rules. 
A third task, known as the Stroop test, targets cognitive inhibition. In this task participants are shown a name of a color, written in a different color, and are asked to identify the color the word is written in. For example, in an incongruent condition, the word blue would be written in green. Individuals with inhibition difficulty should not perform as well as typically developing individuals on this task involving inhibition of the written word.
In this video, we show how to administer the WCST, ToL, and Stroop task to compare flexibility, planning, and inhibition in children with autism spectrum disorder and typically developing counterparts, and explore how each of these groups performs on these different aspects of executive function.

Behavioral Tests to Assess Executive Functions in Children with ASD

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Attention, working-memory, planning, impulse control, ...

Anterograde Amnesia

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Anterograde amnesia is the loss of the ability to form new memories. This can be distinguished from retrograde amnesia, which is the loss of old memories. Anterograde amnesia can result from damage to structures in the brain that are involved in the formation of new memories. Patients who have damage to the structures of the medial temporal lobe, including the hippocampus, amygdala, and the surrounding cortices, often have severe deficits in the formation of certain kinds of memories. These cases can be informative as to how memory is organized in the brain, and how different systems support different kinds of memories. 
In this video, we will test a patient with medial temporal lobe damage on a series of memory tasks designed to distinguish between different forms of memory. First, we will test short-term or working memory, which is the process we use to keep information in mind temporarily. Next, we will test two different forms of long-term memory: explicit and implicit memory. Explicit memories are conscious and easy to verbalize. For example, memories of facts or episodes from our lives are explicit memories. We can easily tell someone what we ate for breakfast, or what city is the capital of France. Implicit memory involves knowledge we gain from experience but that is not easily expressible. For example, knowing how to do things, or becoming habituated to a stimulus are forms of implicit memory. 
These procedures are based in part on studies of the famous patient Henry Molaison, also known by his initials H.M., who had severe anterograde amnesia as a result of a surgery for intractable epilepsy in which parts of both temporal lobes were resected.1 We will perform a test of digit span, which measures short-term memory, a test of paired-associate learning, which measures explicit or declarative memory, and mirror-drawing, a test of implicit skill learning.2

Testing Short- and Long-term Memories in Patients with Brain Injuries

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Anterograde amnesia is the loss of the ability to form ...

Physiological Correlates of Emotion Recognition

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
The autonomic nervous system (ANS) controls the activity of the body's internal organs and regulates changes in their activity depending on the current environment. The vagus nerve, which innervates many of the internal organs, is an important part of the system. When our brain senses danger, vagal tone is inhibited, leading to a set of changes in the body designed to make us more prepared to fight or flee; for example, our heart rate increases, our pupils dilate, and we breath more quickly. Conversely, when the vagal system is activated, these physiological responses are inhibited, leading to a calmer state. The vagus nerve, then, acts as a kind of "brake" on our arousal. One interesting consequence of this calmer state is that it tends to promote social interaction-when we are not tensed and afraid of our immediate environment we are instead receptive to interacting with others. Poor functioning of this regulatory mechanism, therefore, may be associated with difficulties in social behavior.
One index of autonomic regulation is heart rate variability (HRV). HRV is a measure of how much the gap between one beat and the next varies over time. High HRV means there are continual fluctuations in the heart rate over time, a reflection of successful autonomic regulation. Low HRV means there is consistency of the heart rate over time, a condition associated with poor autonomic regulation. 
In this study we will test the hypothesis that increased HRV is associated with more accurate categorization of emotional stimuli.1,2 Following a study by Park et al., we will measure HRV and test its association on a task that measures skill at perceiving facial emotions.3

Correlating Heart Rate Variability with Emotion Recognition

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
The autonomic nervous system (ANS) controls the ...

Event-related Potentials and the Oddball Task

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Given the overwhelming amount of information captured by the sensory organs, it is crucial that the brain is able to prioritize the processing of certain stimuli, to spend less effort on what might not be currently important and to attend to what is. One heuristic the brain uses is to ignore stimuli that are frequent or constant in favor of stimuli that are unexpected or unique. Therefore, rare events tend to be more salient and capture our attention. Furthermore, stimuli that are relevant to our current behavioral goals are prioritized over those that are irrelevant. 
The neurophysiological correlates of attention have been experimentally examined through the use of the oddball paradigm. Originally introduced in 1975, the oddball task presents the participant with a sequence of repetitive audio or visual stimuli, infrequently interrupted by an unexpected stimulus.1 This interruption by a target stimulus has been shown to elicit specific electrical events that are recordable at the scalp known as event-related potentials (ERPs). An ERP is the measured brain response resulting from a specific sensory, cognitive, or motor event. ERPs are measured using electroencephalography (EEG), a noninvasive means of evaluating brain function in patients with disease and normally functioning individuals. A specific ERP component found across the parietal region of the scalp, known as the P300, is enhanced in response to oddball events. The P300 is a positive-going deflection in the EEG signal that occurs about between 250 and 500 ms after stimulus onset. In general, early potentials reflect sensory-motor processing while later potentials like the P300 reflect cognitive processing. 
In this video, we show how to administer the oddball task using EEG. The video will cover the setup and administration of EEG, and analysis of ERPs related to both control and target stimuli in the oddball task. In this task, participants are set up with the EEG electrodes, then brain activity is recorded while they view control stimuli, interspersed with target stimuli. The procedure is similar to that of Habibi et al.2 Each time a target stimulus is presented, the participant presses a button. When the ERPs are averaged across the control and target stimuli, the neural correlates of each event can be compared in a selected time window.

Measuring Event-related Potentials Using EEG in Oddball Task

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Given the overwhelming amount of information captured ...

Language: The N400 in Semantic Incongruity

Source: Laboratories of Sarah I. Gimbel and Jonas T. Kaplan&#8212; University of Southern California
Understanding language is one of the most complex cognitive tasks that humans are capable of. Given the incredible amount of possible choices when combining individual words to form meaning in sentences, it is crucial that the brain is able to identify when words form coherent combinations and when an anomaly appears that undermines meaning. Extensive research has shown that certain scalp-recorded electrical events are sensitive to deviations in this kind of expectation. Importantly, these electrical signatures of incongruity are specific to unexpected meanings, and are therefore different from the brain's general responses to other kinds of anomalies. 
The neurophysiological correlates of semantic incongruity have been experimentally examined through the use of paradigms that present semantically congruent and incongruent ends to sentences. Originally introduced in 1980, the semantic incongruity task presents the participant with a series of sentences that end with either a congruent or incongruent word. To test that the response is from semantic incongruity and not more generally due to surprise, some sentences included words presented in a different size.1 The semantically incongruent end to a sentence has been shown to elicit specific electrical events that are recordable at the scalp known as event-related potentials (ERPs). An ERP is the measured brain response resulting from a specific sensory, cognitive, or motor event. ERPs are measured using electroencephalography (EEG), a noninvasive means of evaluating brain function in patients with disease and normally functioning individuals. A specific ERP component found across the scalp, known as the N400, shows greater amplitude in response to semantically incongruent events. The N400 is a negative-going deflection in the EEG signal that occurs about between 250 and 400 ms after stimulus onset. In general, early potentials reflect sensory-motor processing, while later potentials like the N400 reflect cognitive processing. 
In this video, we show how to administer a semantic incongruity task using EEG. The video will cover the setup and administration of EEG, and analysis of ERPs related to both control and target stimuli in the semantic incongruity. In this task, participants are set up with the EEG electrodes, then brain activity is recorded while they view control sentences and semantically incongruent sentences. The EEG procedure is similar to that of Habibi et al.,1 and the task is modeled after Kutas and Hillyard.2 When the ERPs are averaged across the congruous and incongruous sentences, the neural correlates of each event can be compared in a selected time window.

Studying Language Processing: the N400 in Semantic Incongruity

Source: Laboratories of Sarah I. Gimbel and Jonas T. Kaplan&#8212; University of Southern California
Understanding language is one of the most complex ...

Learning and Memory: The Remember-Know Task

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Our experience of memory is varied and complex. Sometimes we remember events in vivid detail, while other times we may only have a vague sense of familiarity. Memory researchers have made a distinction between memories that are recollected versus those that are familiar. A recollected item is one that is not only remembered, but carries with it details of the time at which it was learned or encoded. Like a recollected item, a familiar item is also remembered, but is void of any details about the circumstances surrounding its encoding. Many studies of recollection and familiarity have focused on the medial temporal lobe (MTL), specifically the hippocampus, since its involvement in memory encoding, consolidation, and retrieval is well-known and well-studied.1-3
This video shows how to administer the Remember-Know task4 to compare brain activation in these two types of memory retrieval. In this context, remember is another term for recollection, while know refers to memories that are familiar but not explicitly recollected. In this version of the Remember-Know task, participants are exposed to a series of color images, and asked to remember what they see. Inside an fMRI scanner, they will be exposed to both images that were studied and to novel images, and they will make a "remember," "know," or "new" judgment about each image, indicating what kind of memory they have for that item. Following the scan, whole brain and hippocampal activity will be examined to determine differential activity related to recollection and familiarity. This study is based on a study performed by Gimbel and Brewer.5

The Remember-Know Task: Memory Recall and Brain Activation

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Our experience of memory is varied and complex. ...

Measuring Grey Matter Differences with Voxel-based Morphometry: The Musical Brain

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Experience shapes the brain. It is well understood that our brains are different as a result of learning. While many experience-related changes manifest themselves at the microscopic level, for example by neurochemical adjustments in the behavior of individual neurons, we may also examine anatomical changes to the structure of the brain at a macroscopic level. One famous example of this kind of change comes from the case of the London taxi drivers, who along with learning the complex routes of the city show larger volume in the hippocampus, a brain structure known to play a role in navigational memory.1
Many traditional methods of examining brain anatomy require painstaking tracing of anatomical regions of interest in order to measure their size. However, using modern neuroimaging techniques, we can now compare the anatomy of the brains across groups of people using automated algorithms. While these techniques do not avail themselves of the sophisticated knowledge that human neuroanatomists may bring to the task, they are quick, and sensitive to very small differences in anatomy. In a structural magnetic resonance image of the brain, the intensity of each volumetric pixel, or voxel, relates to the density of the gray matter in that region. For example, in a T1-weighted MRI scan, very bright voxels are found in locations where there are white matter fiber bundles, while darker voxels correspond to grey matter, where the cell bodies of neurons reside. The technique of quantifying and comparing brain structure on a voxel-by-voxel basis is called voxel-based morphometry, or VBM.2 In VBM, we first register all of the brains to a common space, smoothing over any gross differences in anatomy. We then compare the intensity values of the voxels to identify localized, small scale differences in gray matter density.
In this experiment, we will demonstrate the VBM technique by comparing the brains of musicians with those of non-musicians. Musicians engage in intense motoric, visual, and acoustic training. There is evidence from multiple sources that that the brains of people who have gone through musical training are functionally and structural different from those who haven't. Here, we follow Gaser and Shlaug3 and Bermudez et al.4 in using VBM to identify these structural differences in the brains of musicians.

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Experience shapes the brain. It is well understood ...

Decoding Auditory Imagery with Multivoxel Pattern Analysis

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Imagine the sound of a bell ringing. What is happening in the brain when we conjure up a sound like this in the "mind's ear?" There is growing evidence that the brain uses the same mechanisms for imagination that it uses for perception.1 For example, when imagining visual images, the visual cortex becomes activated, and when imagining sounds, the auditory cortex is engaged. However, to what extent are these activations of sensory cortices specific to the content of our imaginations? 
One technique that can help to answer this question is multivoxel pattern analysis (MPVA), in which functional brain images are analyzed using machine-learning techniques.2-3 In an MPVA experiment, we train a machine-learning algorithm to distinguish among the various patterns of activity evoked by different stimuli. For example, we might ask if imagining the sound of a bell produces different patterns of activity in auditory cortex compared with imagining the sound of a chainsaw, or the sound of a violin. If our classifier learns to tell apart the brain activity patterns produced by these three stimuli, then we can conclude that the auditory cortex is activated in a distinct way by each stimulus. One way to think of this kind of experiment is that instead of asking a question simply about the activity of a brain region, we ask a question about the information content of that region. 
In this experiment, based on Meyer et al., 2010,4 we will cue participants to imagine several sounds by presenting them with silent videos that are likely to evoke auditory imagery. Since we are interested in measuring the subtle patterns evoked by imagination in auditory cortex, it is preferable if the stimuli are presented in complete silence, without interference from the loud noises made by the fMRI scanner. To achieve this, we will use a special kind of functional MRI sequence known as sparse temporal sampling. In this approach, a single fMRI volume is acquired 4-5 s after each stimulus, timed to capture the peak of the hemodynamic response.

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Imagine the sound of a bell ringing. What is happening ...

Visual Attention: fMRI Investigation of Object-based Attentional Control

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212; University of Southern California
The human visual system is incredibly sophisticated and capable of processing large amounts of information very quickly. However, the brain's capacity to process information is not an unlimited resource. Attention, the ability to selectively process information that is relevant to current goals and to ignore information that is not, is therefore an essential part of visual perception. Some aspects of attention are automatic, while others are subject to voluntary, conscious control. In this experiment we explore the mechanisms of voluntary, or "top-down" attentional control on visual processing. 
This experiment leverages the orderly organization of visual cortex to examine how top-down attention can selectively modulate the processing of visual stimuli. Certain regions of the visual cortex appear to be specialized for processing specific visual items. Specifically, work by Kanwisher et al.1 has identified an area in the fusiform gyrus of the inferior temporal lobe that is significantly more active when subjects view faces compared to when they observe other common objects. This area has come to be known as the Fusiform Face Area (FFA). Another brain region, known as the Parahippocampal Place Area (PPA), responds strongly to houses and places, but not to faces.2 Given that we know how these regions respond to specific types of stimuli, their activity can be further explored to identify a key component of vision-visual attention. 
This video shows how to use fMRI to localize the FFA and PPA in the brain, and then examines how object-based attentional control modulates activity in these areas. The use of a functional localizer to restrict subsequent hypothesis testing is a powerful technique in functional imaging. Participants will undergo functional MRI while being presented with an overlaid image of a face and a house. Even though both a face and a house are presented in each stimulus, we predict that patterns of activity in their FFA and PPA will change based on which item is being attended to.3

fMRI Investigation of Object-based Visual Attentional Control

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212; University of Southern California
The human visual system is incredibly sophisticated ...

Using Diffusion Tensor Imaging in Traumatic Brain Injury

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Traditional brain imaging techniques using MRI are very good at visualizing the gross structures of the brain. A structural brain image made with MRI provides high contrast of the borders between gray and white matter, and information about the size and shape of brain structures. However, these images do not detail the underlying structure and integrity of white matter networks in the brain, which consist of axon bundles that interconnect local and distant brain regions.
Diffusion MRI uses pulse sequences that are sensitive to the diffusion of water molecules. By measuring the direction of diffusion, it is possible to make inferences about the structure of white matter networks in the brain. Water molecules within an axon are constrained in their movements by the cell membrane; instead of randomly moving in every direction with equal probability (isotropic movement), they are more likely to move in certain directions, in parallel with the axon (anisotropic movement; Figure 1). Therefore, measures of diffusion anisotropy are thought to reflect properties of the white matter such as fiber density, axon thickness, and degree of myelination. One common measure is fractional anisotropy (FA). FA values range from 0, which represents completely isotropic movement, to 1, reflecting maximum anisotropy.
<img alt="Figure 1" src="/files/ftp_upload/10276/10276fig1.jpg" /> 
Figure 1: Diffusion anisotropy. When the direction of diffusion is unconstrained and random, movement is measured in all directions equally. This is isotropic diffusion (A). When water molecules are contained within the axon of a neuron, diffusion is anisotropic, tending to occur more frequently along the direction of the axon (B). <a href="http://www.jove.com/files/ftp_upload/10276/10276fig1large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
In this experiment we will use diffusion tensor imaging (DTI) to measure white matter integrity in traumatic brain injury (TBI). TBI occurs when an external force injures the brain, such as a blow to the head or a sudden movement like the kind that might occur in a car accident. This type of brain injury from mechanical forces is associated with diffuse axonal injury-damage to white matter throughout the brain. Because it is an injury affecting white matter integrity, standard neuroimaging techniques may not reveal the damage. However, measures of diffusion are especially sensitive to these anatomical changes. Following a study by Kraus et al.1, we compare a group of healthy controls to a group of people with TBI and use diffusion imaging to measure the effect of TBI on cerebral white matter. Furthermore, we will test the relationship between white matter integrity and cognitive function using an attention task.2 This study uses a region of interest (ROI) approach focusing on three white matter tracts: the splenium of the corpus callosum, the anterior corona radiata, and the superior longitudinal fasciculus (Figure 2).
<img alt="Figure 2" src="/files/ftp_upload/10276/10276fig2.jpg" /> 
Figure 2: Regions of interest. The three ROIs, defined from the ICBM DTI-81 atlas, are shown here in horizontal slices through the brain. In green is the splenium of the corpus callosum. The splenium is the most posterior part of the corpus callosum. In blue is the anterior corona radiata. The superior longitudinal fasciculus is shown in red. <a href="http://www.jove.com/files/ftp_upload/10276/10276fig2large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Diffusion Tensor Imaging in Traumatic Brain Injury

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Traditional brain imaging techniques using MRI are ...

Using TMS to Measure Motor Excitability During Action Observation

Source: Laboratories of Jonas T. Kaplan and Sarah I. Gimbel&#8212;University of Southern California
Transcranial Magnetic Stimulation (TMS) is a non-invasive brain stimulation technique that involves passing current through an insulated coil placed against the scalp. A brief magnetic field is created by current in the coil, and because of the physical process of induction, this leads to a current in the nearby neural tissue. Depending on the duration, frequency, and magnitude of these magnetic pulses, the underlying neural circuitry can be affected in many different ways. Here, we demonstrate the technique of single-pulse TMS, in which one brief magnetic pulse is used to stimulate the neocortex.
One observable effect of TMS is that it can produce muscle twitches when applied over the motor cortex. Due to the somatotopic organization of the motor cortex, different muscles can be targeted depending on the precise placement of the coil. The electrical signals that cause these muscle twitches, called motor evoked potentials, or MEPs, can be recorded and quantified by electrodes placed on the skin over the targeted muscle. The amplitude of MEPs can be interpreted to reflect the underlying excitability of the motor cortex; for example, when the motor cortex is activated, observed MEPs are larger. 
In this experiment, based on a study originally performed by Fadiga and colleagues1 and since replicated by many others,2 we use single-pulse TMS to test the excitability of motor cortex during action observation. It is known that motor cortex can be activated not only when we move, but when we watch others perform movements. A common interpretation of this phenomenon is that it reflects a simulation process that may play a role in the understanding of others' actions. Here we will record MEPs evoked by TMS over the primary motor cortex while subjects observe the movements of others compared with control stimuli.

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