The genetic architecture of the human hypothalamus and its involvement in neuropsychiatric behaviours and disorders.

Despite its crucial role in the regulation of vital metabolic and neurological functions, the genetic architecture of the hypothalamus remains unknown. Here we conducted multivariate genome-wide association studies (GWAS) using hypothalamic imaging data from 32,956 individuals to uncover the genetic underpinnings of the hypothalamus and its involvement in neuropsychiatric traits. There were 23 significant loci associated with the whole hypothalamus and its subunits, with functional enrichment for genes involved in intracellular trafficking systems and metabolic processes of steroid-related compounds. The hypothalamus exhibited substantial genetic associations with limbic system structures and neuropsychiatric traits including chronotype, risky behaviour, cognition, satiety and sympathetic-parasympathetic activity. The strongest signal in the primary GWAS, the ADAMTS8 locus, was replicated in three independent datasets (N = 1,685-4,321) and was strengthened after meta-analysis. Exome-wide association analyses added evidence to the association for ADAMTS8, and Mendelian randomization showed lower ADAMTS8 expression with larger hypothalamic volumes. The current study advances our understanding of complex structure-function relationships of the hypothalamus and provides insights into the molecular mechanisms that underlie hypothalamic formation.

Effects of virtual reality on psychophysical measures of pain: superiority to imagination and nonimmersive conditions.

ABSTRACT: Virtual reality (VR) has been shown to be effective in pain management. However, to date, little is known about the mechanisms by which immersive experiences influence pain processing. The aim of this study was to investigate the direct effects of an immersive VR environment on the perception of experimental pain in individuals with chronic pain and pain-free controls. The immersion in a VR landscape was compared with mental imagery and a nonimmersive control condition. Using a randomized within-crossover design, pressure pain detection and tolerance thresholds, spatial and temporal summation (SSP, TSP), and conditioned pain modulation (CPM) were measured in 28 individuals with chronic pain and 31 pain-free controls using phasic cuff pressure on the legs. Direct comparison between the groups showed that although individuals with pain had significantly lower pain thresholds, reduced CPM effects, and increased TSP, the VR condition had the same pain-inhibitory effect on pain thresholds as in pain-free controls. Conditioned pain modulation effects were reduced by all conditions compared with baseline. There were no significant differences between conditions and baseline for TSP and SSP. Overall, pain modulatory effects were largest for VR and smallest for imagery. These results demonstrate that immersion in a VR environment has an increasing effect on pain thresholds, reduces pain inhibition in a CPM paradigm, and has no effects on TSP. This applies for participants with chronic pain and pain-free controls. These VR effects exceeded the effects of mental imagery on the nonimmersive control condition. This indicates that VR effectively modulates pain perception in both patients and controls irrespective of differences in pain perception.

Risk profiles for heavy drinking in adolescence: differential effects of gender.

Abnormalities across different domains of neuropsychological functioning may constitute a risk factor for heavy drinking during adolescence and for developing alcohol use disorders later in life. However, the exact nature of such multi-domain risk profiles is unclear, and it is further unclear whether these risk profiles differ between genders. We combined longitudinal and cross-sectional analyses on the large IMAGEN sample (N ≈ 1000) to predict heavy drinking at age 19 from gray matter volume as well as from psychosocial data at age 14 and 19-for males and females separately. Heavy drinking was associated with reduced gray matter volume in 19-year-olds' bilateral ACC, MPFC, thalamus, middle, medial and superior OFC as well as left amygdala and anterior insula and right inferior OFC. Notably, this lower gray matter volume associated with heavy drinking was stronger in females than in males. In both genders, we observed that impulsivity and facets of novelty seeking at the age of 14 and 19, as well as hopelessness at the age of 14, are risk factors for heavy drinking at the age of 19. Stressful life events with internal (but not external) locus of control were associated with heavy drinking only at age 19. Personality and stress assessment in adolescents may help to better target counseling and prevention programs. This might reduce heavy drinking in adolescents and hence reduce the risk of early brain atrophy, especially in females. In turn, this could additionally reduce the risk of developing alcohol use disorders later in adulthood.

The Effect of Prosthesis Use on Hand Mental Rotation After Unilateral Upper-Limb Amputation.

Amputation of a limb induces changes in the so-called body schema, which might be influenced by the use of prosthetic devices. Changes in the body representation associated with prosthesis use could be investigated using a hand mental rotation task. However, direct neurophysiologic evidence for the effect of prosthesis use on hand mental rotation is still lacking. In this paper, we recruited two groups of unilateral upper-limb amputees, i.e., amputees using a prosthesis or with a history of prosthesis use (Pro group) and amputees without a prosthesis (non-Pro group), as well as a sample of matched healthy controls. Using concurrent behavioral and electrophysiological assessments, we found that Pro amputees were comparable to healthy controls in either behavior or event-related potentials (ERPs), while non-Pro amputees showed prolonged response time as well as divergent ERP patterns. The P200 amplitude of non-Pro amputees was significantly larger for the non-dominant hand pictures than that for the dominant hand pictures, while such a hand difference in P200 was not found in either healthy controls or Pro amputees. Furthermore, the typical angular modulation of the N200 amplitude in healthy controls and Pro amputees was not presented in non-Pro amputees. Our results suggest that prosthesis use could preserve mental rotation ability by maintaining the performance of motor imagery and visual perception of hands, which represents a preservation of the body schema.

Phantom limb perception interferes with motor imagery after unilateral upper-limb amputation.

A potential contributor to impaired motor imagery in amputees is an alteration of the body schema as a result of the presence of a phantom limb. However, the nature of the relationship between motor imagery and phantom experiences remains unknown. In this study, the influence of phantom limb perception on motor imagery was investigated using a hand mental rotation task by means of behavioral and electrophysiological measures. Compared with healthy controls, significantly prolonged response time for both the intact and missing hand were observed specifically in amputees who perceived a phantom limb during the task but not in amputees without phantom limb perception. Event-related desynchronization of EEG in the beta band (beta-ERD) in central and parietal areas showed an angular disparity specifically in amputees with phantom limb perception, with its source localized in the right inferior parietal lobule. The response time as well as the beta-ERD values were significantly positively correlated with phantom vividness. Our results suggest that phantom limb perception during the task is an important interferential factor for motor imagery after amputation and the interference might be related to a change of the body representation resulting from an unnatural posture of the phantom limb.

Illusion-related brain activations: a new virtual reality mirror box system for use during functional magnetic resonance imaging.

Extended viewing of movements of one's intact limb in a mirror as well as motor imagery have been shown to decrease pain in persons with phantom limb pain or complex regional pain syndrome and to increase the movement ability in hemiparesis following stroke. In addition, mirrored movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain. However, using a so-called mirror box has technical limitations, some of which can be overcome by virtual reality applications. We developed a virtual reality mirror box application and evaluated its comparability to a classical mirror box setup. We applied both paradigms to 20 healthy controls and analyzed vividness and authenticity of the illusion as well as brain activation patterns. In both conditions, subjects reported similar intensities for the sensation that movements of the virtual left hand felt as if they were executed by their own left hand. We found activation in the primary sensorimotor cortex contralateral to the actual movement, with stronger activation for the virtual reality 'mirror box' compared to the classical mirror box condition, as well as activation in the primary sensorimotor cortex contralateral to the mirrored/virtual movement. We conclude that a virtual reality application of the mirror box is viable and that it might be useful for future research.

Psychological pain interventions and neurophysiology: implications for a mechanism-based approach.

This article provides an illustrative overview of neurophysiological changes related to acute and chronic pain involving structural and functional brain changes, which might be the targets of psychological interventions. A number of psychological pain treatments have been examined with respect to their effects on brain activity, ranging from cognitive- and operant behavioral interventions, meditation and hypnosis, to neuro- and biofeedback, discrimination training, imagery and mirror treatment, as well as virtual reality and placebo applications. These treatments affect both ascending and descending aspects of pain processing and act through brain mechanisms that involve sensorimotor areas as well as those involved in affective-motivational and cognitive-evaluative aspects. The analysis of neurophysiological changes related to effective psychological pain treatment can help to identify subgroups of patients with chronic pain who might profit from different interventions, can aid in predicting treatment outcome, and can assist in identifying responders and nonresponders, thus enhancing the efficacy and efficiency of psychological interventions. Moreover, new treatment targets can be developed and tested. Finally, the use of neurophysiological measures can also aid in motivating patients to participate in psychological interventions and can increase their acceptance in clinical practice.

An augmented reality home-training system based on the mirror training and imagery approach.

Mirror training and movement imagery have been demonstrated to be effective in treating several clinical conditions, such as phantom limb pain, stroke-induced hemiparesis, and complex regional pain syndrome. This article presents an augmented reality home-training system based on the mirror and imagery treatment approaches for hand training. A head-mounted display equipped with cameras captures one hand held in front of the body, mirrors this hand, and displays it in real time in a set of four different training tasks: (1) flexing fingers in a predefined sequence, (2) moving the hand into a posture fitting into a silhouette template, (3) driving a "Snake" video game with the index finger, and (4) grasping and moving a virtual ball. The system records task performance and transfers these data to a central server via the Internet, allowing monitoring of training progress. We evaluated the system by having 7 healthy participants train with it over the course of ten sessions of 15-min duration. No technical problems emerged during this time. Performance indicators showed that the system achieves a good balance between relatively easy and more challenging tasks and that participants improved significantly over the training sessions. This suggests that the system is well suited to maintain motivation in patients, especially when it is used for a prolonged period of time.

Simultaneous EEG and fMRI reveals a causally connected subcortical-cortical network during reward anticipation.

Electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) have been used to study the neural correlates of reward anticipation, but the interrelation of EEG and fMRI measures remains unknown. The goal of the present study was to investigate this relationship in response to a well established reward anticipation paradigm using simultaneous EEG-fMRI recording in healthy human subjects. Analysis of causal interactions between the thalamus (THAL), ventral-striatum (VS), and supplementary motor area (SMA), using both mediator analysis and dynamic causal modeling, revealed that (1) THAL fMRI blood oxygenation level-dependent (BOLD) activity is mediating intermodal correlations between the EEG contingent negative variation (CNV) signal and the fMRI BOLD signal in SMA and VS, (2) the underlying causal connectivity network consists of top-down regulation from SMA to VS and SMA to THAL along with an excitatory information flow through a THAL→VS→SMA route during reward anticipation, and (3) the EEG CNV signal is best predicted by a combination of THAL fMRI BOLD response and strength of top-down regulation from SMA to VS and SMA to THAL. Collectively, these findings represent a likely neurobiological mechanism mapping a primarily subcortical process, i.e., reward anticipation, onto a cortical signature.

Cortico-subcortical activation patterns for itch and pain imagery.

The imagery of itch and pain evokes emotional responses and covert motor responses (scratching to itch and withdrawal to pain). This suggests some similarity in cerebral mechanisms. However, itch is more socially contagious than pain, as evidenced by the fact that scratching behaviors can be easily initiated by watching itch-inducing situations, whereas withdrawal is less easily initiated by watching painful situations. Thus, we assumed that the cerebral mechanisms of itch imagery partly differ from those of pain imagery in particular with respect to motor regions. We addressed this issue in 18 healthy subjects using functional magnetic resonance imaging. The subjects were instructed to imagine itch and pain sensations in their own bodies while viewing pictures depicting stimuli associated with these sensations. Itch and pain imagery activated the anterior insular cortex (aIC) and motor-related regions such as supplementary motor area, basal ganglia, thalamus, and cerebellum. Activity in these regions was not significantly different between itch and pain imagery. However, functional connectivity between motor-related regions and the aIC showed marked differences between itch and pain imagery. Connectivity with the aIC was stronger in the primary motor and premotor cortices during pain imagery and stronger in the globus pallidus during itch imagery. These findings indicate that brain regions associated with imagery of itch are the same as those involved in imagery of pain, but their functional networks differ. These differences in brain networks may explain why motor responses to itch are more socially contagious than those related to pain.

Site-specific visual feedback reduces pain perception.

One of the most common forms of chronic pain is back pain. Until now, nothing has been known about the influence of visualizing one's own back on pain perception at this site. We tested 18 patients with chronic back pain and 18 healthy controls, by implementing online video feedback of the back during painful pressure and subcutaneous electrical stimuli over the trapezius muscle. Pain threshold and pain tolerance were assessed. Pressure pain stimulation intensity was set to 50% above the pain threshold. Subcutaneous stimulation intensity was set to 70% above the pain threshold. Subjects had to rate pain intensity and unpleasantness after each stimulation block on an 11-point numerical rating scale. Visual feedback of the back reduced perceived pain intensity compared to feedback of the hand in both patients and controls. These findings suggest novel intervention modes for chronic back pain based on visualization of body parts by augmented reality applications.

A target sample of adolescents and reward processing: same neural and behavioral correlates engaged in common paradigms?

Adolescence is a transition period that is assumed to be characterized by increased sensitivity to reward. While there is growing research on reward processing in adolescents, investigations into the engagement of brain regions under different reward-related conditions in one sample of healthy adolescents, especially in a target age group, are missing. We aimed to identify brain regions preferentially activated in a reaction time task (monetary incentive delay (MID) task) and a simple guessing task (SGT) in a sample of 14-year-old adolescents (N = 54) using two commonly used reward paradigms. Functional magnetic resonance imaging was employed during the MID with big versus small versus no win conditions and the SGT with big versus small win and big versus small loss conditions. Analyses focused on changes in blood oxygen level-dependent contrasts during reward and punishment processing in anticipation and feedback phases. We found clear magnitude-sensitive response in reward-related brain regions such as the ventral striatum during anticipation in the MID task, but not in the SGT. This was also true for reaction times. The feedback phase showed clear reward-related, but magnitude-independent, response patterns, for example in the anterior cingulate cortex, in both tasks. Our findings highlight neural and behavioral response patterns engaged in two different reward paradigms in one sample of 14-year-old healthy adolescents and might be important for reference in future studies investigating reward and punishment processing in a target age group.

Mirrored, imagined and executed movements differentially activate sensorimotor cortex in amputees with and without phantom limb pain.

Extended viewing of movements of the intact hand in a mirror as well as motor imagery has been shown to decrease pain in phantom pain patients. We used functional magnetic resonance imaging to assess the neural correlates of mirrored, imagined and executed hand movements in 14 upper extremity amputees - 7 with phantom limb pain (PLP) and 7 without phantom limb pain (non-PLP) and 9 healthy controls (HC). Executed movement activated the contralateral sensorimotor area in all three groups but ipsilateral cortex was only activated in the non-PLP and HC group. Mirrored movements activated the sensorimotor cortex contralateral to the hand seen in the mirror in the non-PLP and the HC but not in the PLP. Imagined movement activated the supplementary motor area in all groups and the contralateral primary sensorimotor cortex in the non-PLP and HC but not in the PLP. Mirror- and movement-related activation in the bilateral sensorimotor cortex in the mirror movement condition and activation in the sensorimotor cortex ipsilateral to the moved hand in the executed movement condition were significantly negatively correlated with the magnitude of phantom limb pain in the amputee group. Further research must identify the causal mechanisms related to mirror treatment, imagined movements or movements of the other hand and associated changes in pain perception.

Functional and structural aspects of tinnitus-related enhancement and suppression of auditory cortex activity.

The steady-state auditory evoked magnetic field was recorded in tinnitus patients and controls, both either musicians or non-musicians, all of them with high-frequency hearing loss. Stimuli were AM-tones with two modulation frequencies and three carrier frequencies matching the "audiometric edge", i.e. the frequency above which hearing loss increases more rapidly, the tinnitus frequency or the frequency 1 1/2 octaves above the audiometric edge in controls, and a frequency 1 1/2 octaves below the audiometric edge. Stimuli equated in carrier frequency, but differing in modulation frequency, were simultaneously presented to the two ears. The modulation frequency-specific components of the dual steady-state response were recovered by bandpass filtering. In both hemispheres, the source amplitude of the response was larger for contralateral than ipsilateral input. In non-musicians with tinnitus, this laterality effect was enhanced in the hemisphere contralateral and reduced in the hemisphere ipsilateral to the tinnitus ear, especially for the tinnitus frequency. The hemisphere-by-input laterality dominance effect was smaller in musicians than in non-musicians. In both patient groups, source amplitude change over time, i.e. amplitude slope, was increasing with tonal frequency for contralateral input and decreasing for ipsilateral input. However, slope was smaller for musicians than non-musicians. In patients, source amplitude was negatively correlated with the MRI-determined volume of the medial partition of Heschl's gyrus. Tinnitus patients show an altered excitatory-inhibitory balance reflecting the downregulation of inhibition and resulting in a steeper dominance hierarchy among simultaneous processes in auditory cortex. Direction and extent of this alteration are modulated by musicality and auditory cortex volume.

Exposure to uncontrollable stress and the postimperative negative variation (PINV): prior control matters.

The main goal of this study was to assess cortical functioning as indexed by the postimperative negative variation (PINV) induced by uncontrollable stress. Sixty-six persons were randomly assigned to three groups who underwent different sequences of stressor controllability. Within an S1-S2 paradigm, one group had initial control over aversive stimulation followed by loss of control and restitution of control. The other groups initially experienced either uncontrollability or controllability followed by a condition of control. Uncontrollable stress significantly enhanced PINV magnitudes independent of preceding control. However, control over aversive stimulation prior to loss of control normalized PINVs during restitution of control. Persons not experiencing prior control showed enhanced PINVs, longer reaction times, and more errors during restitution of control. We conclude that cortical activation changes are linked to the evaluation of instrumental contingencies. However, the exact determination of brain regions involved in the processing of uncontrollable stress needs further investigation.

Altered pain processing in children with migraine: an evoked potential study.

In adults, evidence is accumulating that migraine is associated with altered central processing of pain stimuli and, possibly, changes in the allocation of attentional resources to such stimuli. In pediatric migraine, however, little is known about altered pain processing. We examined 15 children with migraine and 15 controls (age 10-15) in an oddball standards task. Children had to respond to rare targets (tones) and ignore frequent painful (pain threshold) or non-painful mechanical standard stimuli while evoked potentials were obtained. Painful as compared to non-painful stimuli elicited significantly larger N150, P260 and P300 components of the somatosensory evoked potential in all children. The pain-evoked N150 and P260 components did not differ significantly between groups. However, in children with migraine, both painful and non-painful standard stimuli were associated with significantly larger P300 amplitudes at significantly shorter latencies. Perceived intensity of the painful and non-painful stimuli was comparable in both groups. The evoked potentials and reaction times to the target tones did not differ significantly between groups. Habituation across trials was similar in both groups. Hence, children with migraine may display an automatic attentional bias towards painful and potentially painful somatosensory stimuli. Consistent with the psychobiological perspective of chronic pain, such an attentional bias could constitute an important mechanism for migraine becoming a chronic problem.

Psychophysiological responses in patients with fibromyalgia syndrome.

Physical and emotional stress and altered reactivity of the autonomic nervous system have been implicated in the development and maintenance of fibromyalgia syndrome (FMS). This study investigated blood pressure, heart rate (HR), skin conductance levels (SCL), and surface electromyograms (EMG) from the trapezius muscle in 30 FMS patients and 30 age- and sex-matched healthy controls (HCs). All measures were continuously recorded during baseline (BL), social conflict, mental arithmetic, and relaxation tasks. The FMS patients showed significantly higher stress ratings and self-reported stress responses. Baseline EMG levels were significantly lower, and BL HR was significantly elevated. During both stress tasks, HR reactivity was significantly lower, and SCL reactivity was significantly higher in the FMS group. This pattern of low BL muscle tension and high BL HR, along with low HR and high SCL reactivity to stress, is discrepant to other chronic pain syndromes and suggests unique psychophysiological features associated with FMS. Several potential mechanisms for these psychophysiological responses are discussed.

Phantom limb pain: a case of maladaptive CNS plasticity?

Phantom pain refers to pain in a body part that has been amputated or deafferented. It has often been viewed as a type of mental disorder or has been assumed to stem from pathological alterations in the region of the amputation stump. In the past decade, evidence has accumulated that phantom pain might be a phenomenon of the CNS that is related to plastic changes at several levels of the neuraxis and especially the cortex. Here, we discuss the evidence for putative pathophysiological mechanisms with an emphasis on central, and in particular cortical, changes. We cite both animal and human studies and derive suggestions for innovative interventions aimed at alleviating phantom pain.

Auditory discrimination training for the treatment of tinnitus.

This paper presents a series of 12 cases of chronic tinnitus patients who participated in 4 weeks of auditory discrimination training either close to or far removed from the tinnitus frequency. The training was based on the assumption that tinnitus is related to a shift of the representation of the tinnitus frequency in auditory cortex outside of the normal tonotopic map and that training close to but not removed from the tinnitus frequency should result in a reduction in the severity of the tinnitus. Tinnitus severity was measured 4 times per day during the entire treatment and other tinnitus-related variables were assessed 1 week before and 1 month posttreatment. The comparison of the training close to as compared to remote from the tinnitus frequency did not yield a statistically significant difference. However, a post hoc analysis revealed that patients who engaged in regular training as compared to those who practiced irregularly were significantly more successful in reducing tinnitus severity independent of the trained frequencies. Treatment success was best predicted by days of training and general activity levels. The data suggest that auditory discrimination training shows a dose response effect irrespective of training location and that treatment success is also related to psychological variables. For more substantial changes in multiple variables an extended training period with additional consideration of emotional variables would be necessary. In addition, controls for nonspecific training effects need to be implemented.