Anne J. Blood

Intensely pleasurable responses to music correlate with activity in brain regions implicated in reward and emotion

We used positron emission tomography to study neural mechanisms underlying intensely pleasant emotional responses to music. Cerebral blood flow changes were measured in response to subject-selected music that elicited the highly pleasurable experience of “shivers-down-the-spine” or “chills.” Subjective reports of chills were accompanied by changes in heart rate, electromyogram, and respiration. As intensity of these chills increased, cerebral blood flow increases and decreases were observed in brain regions thought to be involved in reward/motivation, emotion, and arousal, including ventral striatum, midbrain, amygdala, orbitofrontal cortex, and ventral medial prefrontal cortex. These brain structures are known to be active in response to other euphoria-inducing stimuli, such as food, sex, and drugs of abuse. This finding links music with biologically relevant, survival-related stimuli via their common recruitment of brain circuitry involved in pleasure and reward.

Emotional responses to pleasant and unpleasant music correlate with activity in paralimbic brain regions.

Neural correlates of the often-powerful emotional responses to music are poorly understood. Here we used positron emission tomography to examine cerebral blood flow (CBF) changes related to affective responses to music. Ten volunteers were scanned while listening to six versions of a novel musical passage varying systematically in degree of dissonance. Reciprocal CBF covariations were observed in several distinct paralimbic and neocortical regions as a function of dissonance and of perceived pleasantness/unpleasantness. The findings suggest that music may recruit neural mechanisms similar to those previously associated with pleasant/unpleasant emotional states, but different from those underlying other components of music perception, and other emotions such as fear.

The pathophysiological basis of dystonias

Dystonias comprise a group of movement disorders that are characterized by involuntary movements and postures. Insight into the nature of neuronal dysfunction has been provided by the identification of genes responsible for primary dystonias, the characterization of animal models and functional evaluations and in vivo brain imaging of patients with dystonia. The data suggest that alterations in neuronal development and communication within the brain create a susceptible substratum for dystonia. Although there is no overt neurodegeneration in most forms of dystonia, there are functional and microstructural brain alterations. Dystonia offers a window into the mechanisms whereby subtle changes in neuronal function, particularly in sensorimotor circuits that are associated with motor learning and memory, can corrupt normal coordination and lead to a disabling motor disorder.

Cannabis Use Is Quantitatively Associated with Nucleus Accumbens and Amygdala Abnormalities in Young Adult Recreational Users

Marijuana is the most commonly used illicit drug in the United States, but little is known about its effects on the human brain, particularly on reward/aversion regions implicated in addiction, such as the nucleus accumbens and amygdala. Animal studies show structural changes in brain regions such as the nucleus accumbens after exposure to Δ9-tetrahydrocannabinol, but less is known about cannabis use and brain morphometry in these regions in humans. We collected high-resolution MRI scans on young adult recreational marijuana users and nonusing controls and conducted three independent analyses of morphometry in these structures: (1) gray matter density using voxel-based morphometry, (2) volume (total brain and regional volumes), and (3) shape (surface morphometry). Gray matter density analyses revealed greater gray matter density in marijuana users than in control participants in the left nucleus accumbens extending to subcallosal cortex, hypothalamus, sublenticular extended amygdala, and left amygdala, even after controlling for age, sex, alcohol use, and cigarette smoking. Trend-level effects were observed for a volume increase in the left nucleus accumbens only. Significant shape differences were detected in the left nucleus accumbens and right amygdala. The left nucleus accumbens showed salient exposure-dependent alterations across all three measures and an altered multimodal relationship across measures in the marijuana group. These data suggest that marijuana exposure, even in young recreational users, is associated with exposure-dependent alterations of the neural matrix of core reward structures and is consistent with animal studies of changes in dendritic arborization.

Microstructural Abnormalities in Subcortical Reward Circuitry of Subjects with Major Depressive Disorder

Background Previous studies of major depressive disorder (MDD) have focused on abnormalities in the prefrontal cortex and medial temporal regions. There has been little investigation in MDD of midbrain and subcortical regions central to reward/aversion function, such as the ventral tegmental area/substantia nigra (VTA/SN), and medial forebrain bundle (MFB). Methodology/Principal Findings We investigated the microstructural integrity of this circuitry using diffusion tensor imaging (DTI) in 22 MDD subjects and compared them with 22 matched healthy control subjects. Fractional anisotropy (FA) values were increased in the right VT and reduced in dorsolateral prefrontal white matter in MDD subjects. Follow-up analysis suggested two distinct subgroups of MDD patients, which exhibited non-overlapping abnormalities in reward/aversion circuitry. The MDD subgroup with abnormal FA values in VT exhibited significantly greater trait anxiety than the subgroup with normal FA values in VT, but the subgroups did not differ in levels of anhedonia, sadness, or overall depression severity. Conclusions/Significance These findings suggest that MDD may be associated with abnormal microstructure in brain reward/aversion regions, and that there may be at least two subtypes of microstructural abnormalities which each impact core symptoms of depression.

Cortical thickness abnormalities in cocaine addiction – a reflection of both drug use and a pre-existing disposition to drug abuse?

The structural effects of cocaine on neural systems mediating cognition and motivation are not well known. By comparing the thickness of neocortical and paralimbic brain regions between cocaine-dependent and matched control subjects, we found that four of 18 a priori regions involved with executive regulation of reward and attention were significantly thinner in addicts. Correlations were significant between thinner prefrontal cortex and reduced keypresses during judgment and decision making of relative preference in addicts, suggesting one basis for restricted behavioral repertoires in drug dependence. Reduced effortful attention performance in addicts also correlated with thinner paralimbic cortices. Some thickness differences in addicts were correlated with cocaine use independent of nicotine and alcohol, but addicts also showed diminished thickness heterogeneity and altered hemispheric thickness asymmetry. These observations suggest that brain structure abnormalities in addicts are related in part to drug use and in part to predisposition toward addiction.

Functional Increases in Cerebral Blood Volume over Somatosensory Cortex

We have examined the relationship between cerebral blood volume (CBV) and electrophysiology over primary somatosensory cortex (S-I) in the rat. We did this by comparing the spatial characteristics and time course of activity-related changes in plasma fluorescence, intrinsic optical reflectance signals, and single unit electrophysiology in S-I to identical stimuli. S-Is of urethane-anesthetized male Sprague–Dawley rats were exposed, and fluorescent Texas Red dextran dye (MW 70,000) was administered intravenously. Subsequently, foredigit electroshock or vibrissal deflection was associated with fluorescence increases over contralateral forelimb or posteromedial barrel subfield cortex. Fluorescence was delayed and prolonged, indicating that CBV increases at 1–1.5 s and peaks 2–2.5 s after the onset of stimulation in both regions. When stimulus intensity was adjusted to produce barely detectable fluorescence foci (10% above background), significant electrophysiologic spiking was seen. At these parameters, fluorescence change overlay areas of increased cortical layer III cell firing on single unit recordings. However, surface boundaries of the smallest observable fluorescence foci at their peak spatial extents consistently overspilled electrophysiologic center receptive fields. Corresponding intrinsic optical reflectance decreases were seen at 610 and 850 nm, exhibiting similar timing and colocalizing closely with fluorescence increase at both wavelengths after identical stimuli. These signals similarly overspilled electrophysiologic activity. Thus, we observed delayed increases in vascular fluorescence (related to CBV) over activated cortex. The smallest detectable fluorescence changes overspilled the center receptive field boundaries and were associated with appreciable electrophysiologic firing. In addition, the striking spatial and temporal similarity between intrinsic optical reflectance and fluorescence activity suggests that changes in intrinsic cortical reflectance are strongly related to changes in CBV.

Basal ganglia activity remains elevated after movement in focal hand dystonia.

Although previous studies of focal hand dystonia have detected cortical sensorimotor abnormalities, little is known about the role of the basal ganglia in this disorder. We report here that when focal hand dystonic patients performed finger‐tapping tasks, functional magnetic resonance imaging showed persisting elevations of basal ganglia activity after the tasks ended. We posit that inhibitory control of the basal ganglia may be faulty in focal hand dystonia, and that the increases we observe in “resting” activity may mask basal ganglia abnormalities in standard imaging contrast analyses.

The evolution of optical signals in human and rodent cortex.

The time course of optical intrinsic signals was examined in order to characterize the evolution of response in human and rodent cortex. Both subtraction/ratio and principal component analyses were used to construct time-course curves. The time course began at a prestimulus baseline, responded with a finite delay, overcompensated, reduced to a maintenance level, and then disappeared. The magnitude, spatial involvement, and principal components demonstrated similar time-course curves both in human and in rodent. For acute stimuli, peak response was reached between 2 and 3 s and returned to baseline by 6 s poststimulation. The shape of the time-course curve is consistent with the need to satisfy neuronal demand and the contributions of vascular smooth muscle properties to the response behavior. The temporal delays and nonlinear phenomena observed in the time-course curves are consistent with a hydraulic model of neurovascular supply/demand behavior.

BDNF, relative preference, and reward circuitry responses to emotional communication†‡§

Brain derived neurotrophic factor (BDNF) regulates neural development and synaptic transmission. We have tested the hypothesis that functional variation in the BDNF gene (Val66Met polymorphism, rs6265) affects brain reward circuitry encoding human judgment and decision‐making regarding relative preference. We quantified relative preference among faces with emotional expressions (angry, fearful, sad, neutral, and happy) by a keypress procedure performed offline to measure effort traded for viewing time. Keypress‐based relative preferences across the ensemble of faces were mirrored significantly by fMRI signal in the orbitofrontal cortex, amygdala, and hippocampus when passively viewing these faces. For these three brain regions, there was also a statistically significant group difference by BDNF genotype in the fMRI responses to the emotional expressions. In comparison with Val/Met heterozygotes, Val/Val individuals preferentially sought exposure to positive emotions (e.g., happy faces) and had stronger regional fMRI activation to aversive stimuli (e.g., angry, fearful, and sad faces). BDNF genotype accounted for ∼30% of the variance in fMRI signal that mirrors keypress responses to these stimuli. This study demonstrates that functional allelic variation in BDNF modulates human brain circuits processing reward/aversion information and relative preference transactions.