Fear expressed towards threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward non-threatening cues is maladaptive and a debilitating dimension of trauma-and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization requires integration of relevant sensory information and motor output. While thalamic and sub-thalamic brain regions play important roles in sensorimotor integration, very little is known about the contribution of these regions to the phenomenon of fear generalization. In this study, we sought to determine whether fear generalization could be modulated by the zona incerta (ZI), a sub-thalamic brain region that influences sensory discrimination, defensive responses, and retrieval of fear memories. To do so, we combined differential intensity-based auditory fear conditioning protocols in mice with C-FOS immunohistochemistry and DREADD-based manipulation of neuronal activity in the ZI. C-FOS immunohistochemistry revealed an inverse relationship between ZI activation and fear generalization -the ZI was less active in animals that generalized fear. In agreement with this relationship, chemogenetic inhibition of the ZI resulted in fear generalization, while chemogenetic activation of the ZI suppressed fear generalization. Furthermore, targeted stimulation of GABAergic cells in the ZI reduced fear generalization. To conclude, our data suggest that stimulation of the ZI could be used to treat fear generalization in the context of trauma-and anxiety-related disorders.

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Fear expressed toward threat-associated stimuli is an adaptive behavioral response. In contrast, the generalization of fear responses toward nonthreatening cues is a maladaptive and debilitating dimension of trauma-and anxiety-related disorders. Expressing fear to appropriate stimuli and suppressing fear generalization require integration of relevant sensory information and motor output. While thalamic and subthalamic brain regions play important roles in sensorimotor integration, very little is known about the contribution of these regions to the phenomenon of fear generalization. In this study, we sought to determine whether fear generalization could be modulated by the zona incerta (ZI), a subthalamic brain region that influences sensory discrimination, defensive responses, and retrieval of fear memories. To do so, we combined differential intensity-based auditory fear conditioning protocols in mice with C-FOS immunohistochemistry and designer receptors exclusively activated by designer drugs (DREADDs)-based manipulation of neuronal activity in the ZI. C-FOS immunohistochemistry revealed an inverse relationship between ZI activation and fear generalization: The ZI was less active in animals that generalized fear. In agreement with this relationship, chemogenetic inhibition of the ZI resulted in fear generalization, while chemogenetic activation of the ZI suppressed fear generalization. Furthermore, targeted stimulation of GABAergic cells in the ZI reduced fear generalization. To conclude, our data suggest that stimulation of the ZI could be used to treat fear generalization in the context of trauma-and anxiety-related disorders. trauma | posttraumatic stress disorder | subthalamic | fear inhibition | anxiety E xpressing fear toward cues that have previously been associated with trauma is adaptive (conditioned fear). Equally adaptive is the expression of fear toward stimuli that closely resemble traumatic cues (fear generalization). Such generalization of fear allows the organism to be "better safe than sorry." However, fear generalization can diminish quality of life and is a highly debilitating dimension of trauma-and anxiety-related disorders like posttraumatic stress disorder and generalized anxiety disorder (1-4). Reducing fear generalization, while maintaining adaptive fear responses, will reduce the daily burden experienced by individuals living with these disorders and requires identifying neural circuitry that could modulate fear generalization.Brain regions such as the lateral amygdala (5-7), central amygdala (8,9), prefrontal cortex (10, 11), hippocampus (3, 12), and bed nucleus of the stria terminalis (13, 14) have been implicated in fear generalization. More importantly, these regions play crucial roles in detecting threats and assigning valence to environmental stimuli (15-18). Therefore, while manipulating these regions could potentially reduce fear generalization, doing so might compromise threat detection, conditioned fear, and survival. In this study, we set out to ask whether targeting brain ...

Objective: To examine associations between pre-existing migraines and postconcussion symptoms and cognitive performance acutely (within 72 hours) after a suspected concussion. Design: Nested case–control study. Setting: High schools in Maine, USA. Participants: From a sample of 39 161 adolescent athletes who underwent baseline preseason testing, 633 were assessed within 3 days of a suspected concussion. Of these, 59 reported a history of treatment for migraines at baseline (9.3%). These athletes were individually matched to 2 athletes who had a suspected concussion but denied preinjury migraines (total N = 177; age: M = 15.8, SD = 1.3). Assessment of Risk Factors: Self-reported history of treatment for migraines by a physician. Main Outcome Measures: Post-Concussion Symptom Scale total score, ImPACT composite scores, and individual symptom endorsement. Results: Individuals with a pre-existing migraine disorder endorsed greater symptom severity (M = 8.4, SD = 9.9) compared with controls (M = 4.5, SD = 6.5; Cohen's d = 0.47) at preinjury baseline and acutely after suspected injury (migraine: M = 26.0, SD = 25.5; controls: M = 16.7, SD = 15.4; d = 0.44). Acutely after a suspected concussion, greater proportions of athletes with migraine disorders reported mental fogginess (49.2% vs 33.9%) and memory problems (39.0% vs 24.6%; P < 0.05). Baseline ImPACT composite scores were similar between migraine and control groups (d = 0.04-0.13). Adolescents with pre-existing migraine disorders performed worse after a suspected concussion compared with the control participants on verbal memory (F = 4.32, P = 0.041) and visual memory (F = 3.95, P = 0.049). Conclusions: Individuals with pre-existing migraine disorders may be at higher risk for worse outcomes, including greater overall burden of symptoms and worse cognitive functioning in the memory domain, in the first 72 hours after concussion.

Posttraumatic stress disorder (PTSD) is prevalent and associated with significant morbidity. Mild traumatic brain injury (mTBI) concurrent with psychiatric trauma may be associated with PTSD. Prior studies of PTSD‐related structural brain alterations have focused on military populations. The current study examined correlations between PTSD, acute mTBI, and structural brain alterations longitudinally in civilian patients (N = 504) who experienced a recent Criterion A traumatic event. Participants who reported loss of consciousness (LOC) were characterized as having mTBI; all others were included in the control group. PTSD symptoms were assessed at enrollment and over the following year; a subset of participants (n = 89) underwent volumetric brain MRI (M = 53 days posttrauma). Classes of PTSD symptom trajectories were modeled using latent growth mixture modeling. Associations between PTSD symptom trajectories and cortical thicknesses or subcortical volumes were assessed using a moderator‐based regression. mTBI with LOC during trauma was positively correlated with the likelihood of developing a chronic PTSD symptom trajectory. mTBI showed significant interactions with cortical thickness in the rostral anterior cingulate cortex (rACC) in predicting PTSD symptoms, r = .461–.463. Bilateral rACC thickness positively predicted PTSD symptoms but only among participants who endorsed LOC, p < .001. The results demonstrate positive correlations between mTBI with LOC and PTSD symptom trajectories, and findings related to mTBI with LOC and rACC thickness interactions in predicting subsequent chronic PTSD symptoms suggest the importance of further understanding the role of mTBI in the context of PTSD to inform intervention and risk stratification.