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BackgroundBrain volumes in regions such as the hippocampus and amygdala have been associated with risk for the development of posttraumatic stress disorder (PTSD). The objective of this study was to determine whether a set of regional brain volumes, measured by magnetic resonance imaging at 2 weeks following mild traumatic brain injury, were predictive of PTSD at 3 and 6 months after injury.MethodsUsing data from TRACK-TBI (Transforming Research and Clinical Knowledge in TBI), we included patients (N = 421) with Glasgow Coma Scale scores 13-15 assessed after evaluation in the emergency department and at 2 weeks, 3 months, and 6 months after injury. Probable PTSD diagnosis (PTSD Checklist for DSM-5 score, ≥33) was the outcome. FreeSurfer 6.0 was used to perform volumetric analysis of three-dimensional T1-weighted magnetic resonance images at 3T obtained 2 weeks post injury. Brain regions selected a priori for volumetric analyses were insula, hippocampus, amygdala, superior frontal cortex, rostral and caudal anterior cingulate, and lateral and medial orbitofrontal cortices.ResultsOverall, 77 (18.3%) and 70 (16.6%) patients had probable PTSD at 3 and 6 months. A composite volume derived as the first principal component incorporating 73.8% of the variance in insula, superior frontal cortex, and rostral and caudal cingulate contributed to the prediction of 3-month (but not 6-month) PTSD in multivariable models incorporating other established risk factors.ConclusionsResults, while needing replication, provide support for a brain reserve hypothesis of PTSD and proof of principle for how prediction of at-risk individuals might be accomplished to enhance prognostic accuracy and enrich clinical prevention trials for individuals at the highest risk of PTSD following mild traumatic brain injury.

The nucleus accumbens (NAc) has been implicated in sleep, reward, and pain modulation, but the relationship between these functional roles is unclear. This study aimed to determine whether NAc function at the onset and offset of a noxious thermal stimulus is enhanced by rewarding music, and whether that effect is reversed by experimental sleep disruption. Twenty-one healthy subjects underwent functional magnetic resonance imaging scans on 2 separate days after both uninterrupted sleep and experimental sleep disruption. During functional magnetic resonance imaging scans, participants experienced noxious stimulation while listening to individualized rewarding or neutral music. Behavioral results revealed that rewarding music significantly reduced pain intensity compared with neutral music, and disrupted sleep was associated with decreased pain intensity in the context of listening to music. In whole-brain family-wise error cluster-corrected analysis, the NAc was activated at pain onset, but not during tonic pain or at pain offset. Sleep disruption attenuated NAc activation at pain onset and during tonic pain. Rewarding music altered NAc connectivity with key nodes of the corticostriatal circuits during pain onset. Sleep disruption increased reward-related connectivity between the NAc and the anterior midcingulate cortex at pain onset. This study thus indicates that experimental sleep disruption modulates NAc function during the onset of pain in a manner that may be conditional on the presence of competing reward-related stimuli. These findings point to potential mechanisms for the interaction between sleep, reward, and pain, and suggest that sleep disruption affects both the detection and processing of aversive stimuli that may have important implications for chronic pain.

Neurons throughout frontal cortex show robust responses to rewards, but a challenge is determining the specific function served by these different reward signals. Most neuropsychiatric disorders involve dysfunction of circuits between frontal cortex and subcortical structures, such as the striatum. There are multiple frontostriatal loops, and different neuropsychiatric disorders involve different loops to greater or lesser extents. Understanding the role of reward in each of these different circuits is a necessary step in developing novel treatments for these disorders. This chapter summarizes the recent literature that has identified the role of reward in different subregions of the frontal cortex. Orbitofrontal cortex integrates information about multiple aspects of expected rewards in order to derive their value, which can then be used to decide between alternative potential rewards. Neurons in anterior cingulate cortex encode the difference between the expected reward and the actual outcome. This information is useful for learning, since it can ensure that behavior changes when the outcome was not anticipated. Reward also affects signals in lateral prefrontal cortex related to attention and response selection, ensuring that behaviors are optimally prioritized. Finally, the chapter discusses how reward signals contribute to social processing and autonomic control.

Children with long-standing obstructive sleep apnea (OSA) show evidence of neural injury and functional deficits in behavioral and cognitive regulatory brain regions that are reflected in symptoms of altered cognitive performance and behaviors. While we earlier showed reduced gray matter volume and increased and reduced regional cortical thicknesses, such structural changes give little indication of the underlying pathology. Brain tissue integrity in pediatric OSA subjects can reflect the nature and extent of injury or structural adaptation, and can be assessed by entropy tissue texture, a measure of local changes in signal intensity patterns from high-resolution magnetic resonance images. We collected high-resolution T1-weighted magnetic resonance images from 10 pediatric OSA (age, 7.9 ± 1.1 years; apnea-hypopnea-index, 8.8 ± 3.0 events/hour; body-mass-index, 20 ± 6.7 kg/m2; 7 male) and 8 healthy controls (age, 8.8 ± 1.6 years; body-mass-index, 19.6 ± 5.9 kg/m2; 5 female). Images were bias-corrected and entropy maps calculated, individual maps were normalized to a common space, smoothed, and compared between groups (ANCOVA; covariates: age, gender; SPM12, uncorrected-threshold p

ObjectiveGeneralized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms.MethodsHigh-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P

ObjectiveGeneralized tonic-clonic seizures are accompanied by cardiovascular and respiratory sequelae that threaten survival. The frequency of these seizures is a major risk factor for sudden unexpected death in epilepsy (SUDEP), a leading cause of untimely death in epilepsy. The circumstances accompanying such fatal events suggest a cardiovascular or respiratory failure induced by unknown neural processes rather than an inherent cardiac or lung deficiency. Certain cortical regions, especially the insular, cingulate, and orbitofrontal cortices, are key structures that integrate sensory input and influence diencephalic and brainstem regions regulating blood pressure, cardiac rhythm, and respiration; output from those cortical regions compromised by epilepsy-associated injury may lead to cardiorespiratory dysregulation. The aim here was to assess changes in cortical integrity, reflected as cortical thickness, relative to healthy controls. Cortical alterations in areas that influence cardiorespiratory action could contribute to SUDEP mechanisms.MethodsHigh-resolution T1-weighted images were collected with a 3.0-Tesla MRI scanner from 53 patients with generalized tonic-clonic seizures (Mean age ± SD: 37.1 ± 12.6 years, 22 male) at Case Western Reserve University, University College London, and the University of California at Los Angeles. Control data included 530 healthy individuals (37.1 ± 12.6 years; 220 male) from UCLA and two open access databases (OASIS and IXI). Cortical thickness group differences were assessed at all non-cerebellar brain surface locations (P

Theta may play a central role during language understanding and other extended cognitive processing, providing an envelope for widespread integration of participating cortical areas. We used linear microelectrode arrays in epileptics to define the circuits generating theta in inferotemporal, perirhinal, entorhinal, prefrontal and anterior cingulate cortices. In all locations, theta was generated by excitatory current sinks in middle layers which receive predominantly feedforward inputs, alternating with sinks in superficial layers which receive mainly feedback/associative inputs. Baseline and event-related theta were generated by indistinguishable laminar profiles of transmembrane currents and unit-firing. Word presentation could reset theta phase, permitting theta to contribute to late event-related potentials, even when theta power decreases relative to baseline. Limited recordings during sentence reading are consistent with rhythmic theta activity entrained by a given word modulating the neural background for the following word. These findings show that theta occurs spontaneously, and can be momentarily suppressed, reset and synchronized by words. Theta represents an alternation between feedforward/divergent and associative/convergent processing modes that may temporally organize sustained processing and optimize the timing of memory formation. We suggest that words are initially encoded via a ventral feedforward stream which is lexicosemantic in the anteroventral temporal lobe; its arrival may trigger a widespread theta rhythm which integrates the word within a larger context.

Adults recovered from Anorexia nervosa (AN) have altered reward modulation within striatal limbic regions associated with the emotional significance of stimuli, and executive regions concerned with planning and consequences. We hypothesized that adolescents with AN would show similar disturbed reward modulation within the striatum and the anterior cingulate cortex, a region connected to the striatum and involved in reward-guided action selection. Using functional magnetic resonance imaging, twenty-two adolescent females (10 restricting-type AN, 12 healthy volunteers) performed a monetary guessing task. Time series data associated with monetary wins and losses within striatal and cingulate regions of interest were subjected to a linear mixed effects analysis. All participants responded more strongly to wins versus losses in limbic and anterior executive striatal territories. However, AN participants exhibited an exaggerated response to losses compared to wins in posterior executive and sensorimotor striatal regions, suggesting altered function in circuitry responsible for coding the affective context of stimuli and action selection based upon these valuations. As AN individuals are particularly sensitive to criticism, failure, and making mistakes, these findings may reflect the neural processes responsible for a bias in those with AN to exaggerate negative consequences.

Evaluating external and internal stimuli is critical to survival. Potentially tissue-damaging conditions generate sensory experiences that the organism must respond to in an appropriate, adaptive manner (e.g., withdrawal from the noxious stimulus, if possible, or seeking relief from pain and discomfort). The importance we assign to a signal generated by a noxious state, its salience, reflects our belief as to how likely the underlying situation is to impact our chance of survival. Importantly, it has been hypothesized that aberrant functioning of the brain circuits which assign salience values to stimuli may contribute to chronic pain. We describe examples of this phenomenon, including 'feeling pain' in the absence of a painful stimulus, reporting minimal pain in the setting of major trauma, having an 'analgesic' response in the absence of an active treatment, or reporting no pain relief after administration of a potent analgesic medication, which may provide critical insights into the role that salience circuits play in contributing to numerous conditions characterized by persistent pain. Collectively, a refined understanding of abnormal activity or connectivity of elements within the salience network may allow us to more effectively target interventions to relevant components of this network in patients with chronic pain.

Many structural brain asymmetries accompany left hemisphere language dominance. For example, the cingulate sulcus is larger in the medial cortex of the right hemisphere, while the more dorsal paracingulate sulcus is larger on the left. The functional significance of these asymmetries is unknown because fMRI studies rarely attempt to localize activation to specific sulci, possibly due to difficulties in consistent sulcal identification. In medial cortex, for example, there are many regions of partial sulcal overlap where MRI images do not provide sufficient information to unambiguously distinguish a paracingulate sulcus from a displaced anterior cingulate segment. As large samples of postmortem material are rarely available for cytoarchitectural studies of sulcal variation, we have investigated the effect of variation in boundary and sulcal definition on paracingulate asymmetry in the MRI scans of 200 healthy adults (100 men, 100 women). Although women displayed a reliable asymmetry in the size of the paracingulate sulcus, regardless of boundary definition or technique, asymmetry was greatest when (1) the measurement was limited to the midcingulate region between the genu and the anterior commissure; and (2) the more dorsal of two overlapping sulci was always classified as a paracingulate sulcus (rather than as a displaced cingulate segment). The fact that paracingulate asymmetry is maximal in the midcingulate region suggests that this region may play a particular role in hemispheric specialization for language. Future work should investigate the structural and functional correlates of sulcal variation in this region.

Many structural brain asymmetries accompany left hemisphere language dominance. For example, the cingulate sulcus is larger in the medial cortex of the right hemisphere, while the more dorsal paracingulate sulcus is larger on the left. The functional significance of these asymmetries is unknown because fMRI studies rarely attempt to localize activation to specific sulci, possibly due to difficulties in consistent sulcal identification. In medial cortex, for example, there are many regions of partial sulcal overlap where MRI images do not provide sufficient information to unambiguously distinguish a paracingulate sulcus from a displaced anterior cingulate segment. As large samples of postmortem material are rarely available for cytoarchitectural studies of sulcal variation, we have investigated the effect of variation in boundary and sulcal definition on paracingulate asymmetry in the MRI scans of 200 healthy adults (100 men, 100 women). Although women displayed a reliable asymmetry in the size of the paracingulate sulcus, regardless of boundary definition or technique, asymmetry was greatest when (1) the measurement was limited to the midcingulate region between the genu and the anterior commissure; and (2) the more dorsal of two overlapping sulci was always classified as a paracingulate sulcus (rather than as a displaced cingulate segment). The fact that paracingulate asymmetry is maximal in the midcingulate region suggests that this region may play a particular role in hemispheric specialization for language. Future work should investigate the structural and functional correlates of sulcal variation in this region.