Ilhyang Kang

Recovery from Posttraumatic Stress Requires Dynamic and Sequential Shifts in Amygdalar Connectivities

The neural mechanisms underlying the development and maintenance of posttraumatic stress disorder (PTSD) have long been studied. However, little is known about the neural correlates of the recovery process from PTSD. A 5-year longitudinal study was conducted to investigate the trajectory of structural connectivities of the amygdala in disaster survivors with PTSD. Thirty disaster survivors, who were diagnosed with PTSD, and 29 healthy individuals, who were not exposed to trauma, underwent three waves of assessments including neuroimaging scanning over a 5-year period from the time of the disaster at approximately 1.3-year intervals. All disaster survivors showed significant improvements in PTSD symptoms over time. Using diffusion tensor imaging analysis, a 5-year trajectory of amygdalar structural connectivities with key brain regions was assessed. The amygdala–insula connection was initially strengthened and then normalized during recovery, while the amygdala–prefrontal cortex (PFC) connection was at first unaffected, then strengthened, and eventually normalized. The lower tract strength of the amygdala–thalamus connection normalized during recovery, while that of amygdala–hippocampus connection remained low. The greater amygdala–PFC connectivity was associated with less PTSD symptom severity. The present longitudinal study revealed that recovery from PTSD parallels dynamic and sequential shifts in amygdalar connectivities with multiple brain regions, suggesting the expanded view of fear circuitry including the insula and thalamus, beyond the traditional model which primarily involves the amygdala, PFC, and hippocampus.

Metabolic alterations in the anterior cingulate cortex and related cognitive deficits in late adolescent methamphetamine users

The adolescent brain, with ongoing prefrontal maturation, may be more vulnerable to drug use‐related neurotoxic changes as compared to the adult brain. We investigated whether the use of methamphetamine (MA), a highly addictive psychostimulant, during adolescence affect metabolic and cognitive functions of the anterior cingulate cortex (ACC). In adolescent MA users (n = 44) and healthy adolescents (n = 53), the levels of N‐acetyl aspartate (NAA), a neuronal marker, were examined in the ACC using proton magnetic resonance spectroscopy. The Stroop color–word task was used to assess Stroop interference, which may reflect cognitive functions of behavior monitoring and response selection that are mediated by the ACC. Adolescent MA users had lower NAA levels in the ACC (t = −2.88, P = 0.005) and relatively higher interference scores (t = 2.03, P = 0.045) than healthy adolescents. Moreover, there were significant relationships between lower NAA levels in the ACC and worse interference scores in adolescent MA users (r = −0.61, P < 0.001). Interestingly, early onset of MA use, as compared to late onset, was related to both lower NAA levels in the ACC (t = −2.24, P = 0.03) as well as lower performance on interference measure of the Stroop color–word task (t = 2.25, P = 0.03). The current findings suggest that metabolic dysfunction in the ACC and its related cognitive impairment may play an important role in adolescent‐onset addiction, particularly during early adolescence.

Validation of the Korean version of the Connor–Davidson Resilience Scale-2 in firefighters and rescue workers

OBJECTIVE Resilience has been considered as a protective factor against stress. Evaluating resilience in firefighters and rescue workers, who are frequently exposed to traumatic events, is important and relevant. This study examined the psychometric properties of the Korean version of the Connor-Davidson Resilience Scale-2 (CD-RISC2). METHODS Two-hundred twenty-two current professional firefighters and rescue workers were assessed by standardized, semi-structured clinical interviews and self-report questionnaires. Internal consistency, correlation with the CD-RISC, convergent validity, divergent validity, and predictive validity of posttraumatic stress disorder (PTSD) symptom severity were analyzed. RESULTS The CD-RISC2 demonstrated good internal consistency (α=0.75), item-total correlation (r=0.89-0.90), and convergent and divergent validity. The total score of the CD-RISC2 showed significant correlations with the subtotal of the remaining 23 CD-RISC items (r=0.77, p<0.001) and with the score of each CD-RISC item (r=0.15-0.66, all p<0.05). The magnitude of the relationship between the number of traumatic experiences and PTSD symptom severity was greater in the low resilience group than in the high resilience group (p for interaction=0.002). The likelihood-ratio test confirmed that the model predicting PTSD symptom severity based on the CD-RISC2 total score was not improved by the inclusion of subtotal scores of the remaining 23 CD-RISC items (χ(2)=0.31, p=0.58). CONCLUSIONS These results suggest that the CD-RISC2 would be a valuable tool in evaluating resilience quickly and efficiently in firefighters and rescue workers.

Astrocytic water channel aquaporin-4 modulates brain plasticity in both mice and humans: a potential gliogenetic mechanism underlying language-associated learning

The role of astrocytes in brain plasticity has not been extensively studied compared with that of neurons. Here we adopted integrative translational and reverse-translational approaches to explore the role of an astrocyte-specific major water channel in the brain, aquaporin-4 (AQP4), in brain plasticity and learning. We initially identified the most prevalent genetic variant of AQP4 (single nucleotide polymorphism of rs162008 with C or T variation, which has a minor allele frequency of 0.21) from a human database (n=60 706) and examined its functionality in modulating the expression level of AQP4 in an in vitro luciferase reporter assay. In the following experiments, AQP4 knock-down in mice not only impaired hippocampal volumetric plasticity after exposure to enriched environment but also caused loss of long-term potentiation after theta-burst stimulation. In humans, there was a cross-sectional association of rs162008 with gray matter (GM) volume variation in cortices, including the vicinity of the Perisylvian heteromodal language area (Sample 1, n=650). GM volume variation in these brain regions was positively associated with the semantic verbal fluency. In a prospective follow-up study (Sample 2, n=45), the effects of an intensive 5-week foreign language (English) learning experience on regional GM volume increase were modulated by this AQP4 variant, which was also associated with verbal learning capacity change. We then delineated in mice mechanisms that included AQP4-dependent transient astrocytic volume changes and astrocytic structural elaboration. We believe our study provides the first integrative evidence for a gliogenetic basis that involves AQP4, underlying language-associated brain plasticity.

Firefighters, posttraumatic stress disorder, and barriers to treatment: Results from a nationwide total population survey

Repeated exposure to traumatic experiences may put professional firefighters at increased risk of developing posttraumatic stress disorder (PTSD). To date, however, the rate of PTSD symptoms, unmet need for mental health treatment, and barriers to treatment have only been investigated in subsamples rather than the total population of firefighters. We conducted a nationwide, total population-based survey of all currently employed South Korean firefighters (n = 39,562). The overall response rate was 93.8% (n = 37,093), with 68.0% (n = 26,887) complete responses for all variables. The rate of current probable PTSD was estimated as 5.4%. Among those with current probable PTSD (n = 1,995), only a small proportion (9.7%) had received mental health treatment during the past month. For those who had not received treatment, perceived barriers of accessibility to treatment (29.3%) and concerns about potential stigma (33.8%) were reasons for not receiving treatment. Although those with higher PTSD symptom severity and functional impairment were more likely to seek treatment, greater symptom severity and functional impairment were most strongly associated with increased concerns about potential stigma. This nationwide study points to the need for new approaches to promote access to mental health treatment in professional firefighters.

Psychometric Properties of the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) in Public First Responders

ABSTRACT Problematic alcohol consumption is prevalent among first responders because alcohol is commonly used to cope with occupational stress and frequent exposure to traumatic incidents, making them an at-risk population for alcohol use disorders (AUD). This study investigated the psychometric properties of the Korean version of the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) among public first responders. The Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders-IV-Text Revision (SCID), AUDIT-C, AUDIT, and CAGE were administered to 222 public first responders, who were recruited by convenience sampling. One-week test–retest reliability was evaluated in a subsample (n = 24). Receiver operating characteristic (ROC) curve analyses were conducted to evaluate the diagnostic accuracy and estimate the optimal cut-off scores for any AUD and alcohol dependence. Three different analytic criteria were utilized to calculate the cut-off scores. The AUDIT-C demonstrated good test–retest reliability (intraclass correlation coefficient for test–retest reliability = 0.91) and satisfactory convergent validity. The areas under the ROC curves for any AUD and alcohol dependence of the AUDIT-C were 0.87 and 0.93, respectively. For any AUD, all three criteria suggested a cut-off score of 7.5 (sensitivity = 81.8%, specificity = 79.8%), whereas for alcohol dependence, a cut-off score of 8.5 (sensitivity = 85.7%, specificity = 86.1%) was derived from two criteria. In conclusion, the AUDIT-C demonstrated good reliability and validity and proved to be a brief and effective screening test for AUD among first responders.

Altered attentional control over the salience network in complex regional pain syndrome

The degree and salience of pain have been known to be constantly monitored and modulated by the brain. In the case of maladaptive neural responses as reported in centralized pain conditions such as complex regional pain syndrome (CRPS), the perception of pain is amplified and remains elevated even without sustained peripheral pain inputs. Given that the attentional state of the brain greatly influences the perception and interpretation of pain, we investigated the role of the attention network and its dynamic interactions with other pain-related networks of the brain in CRPS. We examined alterations in the intra- and inter-network functional connectivities in 21 individuals with CRPS and 49 controls. CRPS-related reduction in intra-network functional connectivity was found in the attention network. Individuals with CRPS had greater inter-network connectivities between the attention and salience networks as compared with healthy controls. Furthermore, individuals within the CRPS group with high levels of pain catastrophizing showed greater inter-network connectivities between the attention and salience networks. Taken together, the current findings suggest that these altered connectivities may be potentially associated with the maladaptive pain coping as found in CRPS patients.

Brain structural changes in cynomolgus monkeys administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A longitudinal voxel-based morphometry and diffusion tensor imaging study

In animal models of Parkinsons disease (PD), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. However, brain structural changes in response to MPTP remain unclear. This study aimed to investigate in vivo longitudinal changes in gray matter (GM) volume and white matter (WM) microstructure in primate models administered with MPTP. In six cynomolgus monkeys, high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans were acquired 7 times over 32 weeks, and assessments of motor symptoms were conducted over 15 months, before and after the MPTP injection. Changes in GM volume and WM microstructure were estimated on a voxel-by-voxel basis. Mixed-effects regression models were used to examine the trajectories of these structural changes. GM volume initially increased after the MPTP injection and gradually decreased in the striatum, midbrain, and other dopaminergic areas. The cerebellar volume temporarily decreased and returned to its baseline level. The rate of midbrain volume increase was positively correlated with the increase rate of motor symptom severity (Spearman rho = 0.93, p = 0.008). Mean, axial, and radial diffusivity in the striatum and frontal areas demonstrated initial increases and subsequent decreases. The current multi-modal imaging study of MPTP-administered monkeys revealed widespread and dynamic structural changes not only in the nigrostriatal pathway but also in other cortical, subcortical, and cerebellar areas. Our findings may suggest the need to further investigate the roles of inflammatory reactions and glial activation as potential underlying mechanisms of these structural changes.

Brain Perfusion Correlates of Apathy in Alzheimer's Disease

Background and Purpose Apathy is one of the most common neuropsychiatric symptoms in patients with Alzheimers disease (AD). It may have adverse impacts on the progression of AD. However, its neurobiological underpinnings remain unclear. The objective of this study was to investigate differences in regional cerebral blood flow (rCBF) between AD patients with apathy and those without apathy. Methods Sixty-six apathetic AD patients and 66 AD patients without apathy completed Neuropsychiatric Inventory (NPI) and underwent technetium-99m hexamethylpropylene amine oxime single-photon emission computed tomography (SPECT) scans. Voxel-wise differences in rCBF between the 2 groups were examined. Association between rCBF and levels of apathy in the apathetic group was also assessed. Results AD patients with apathy showed lower rCBF in the bilateral orbitofrontal cortex, left putamen, left nucleus accumbens, left thalamus, and bilateral insula than those without (all p<0.005). Mean perfusion across all significant clusters showed a negative linear correlation with NPI apathy score in AD patients with apathy (β=−0.25; p=0.04). Conclusions Hypoperfusion in the prefrontal, striatal, and insular areas may be neural correlates of apathy in AD patients.

Alterations in structural rich-club connectivity of the precuneus are associated with depressive symptoms among individuals with subjective memory complaints

The association between subjective memory complaints (SMCs) and depressive symptoms has been widely reported and both have been regarded as risk factors for dementia, such as Alzheimer’s disease (AD). Although SMCs arise as early as in middle age, the exact neural correlates of comorbid depressive symptoms among individuals who are middle-aged and with SMCs have not yet been well investigated. Because rich-club organization of the brain plays a key role in the pathophysiology of various neuropsychiatric disorders, the investigation of rich club organization may provide insight regarding the neurobiological mechanisms of depressive symptoms in SMCs. In the current study, we compared the rich-club organization in the structural brain connectivity between individuals who have SMCs along with depressive symptoms (SMCD) and individuals with SMCs but without depressive symptoms (SMCO). A total of 53 individuals with SMCD and 91 individuals with SMCO participated in the study. For all participants, high-resolution, T1-weighted images and diffusion tensor images were obtained, and the network analysis was performed. Individuals with SMCD had lower connectivity strength between the precuneus and other rich-club nodes than those with SMCO, which was significant after adjusting for potential confounders. Our findings suggest that disruptions of rich-club connectivity strength of the precuenus are associated with depressive symptoms in middle-aged individuals with SMCs. Given that the precuneus is one of the commonly affected regions in the early stages of AD, our findings may imply that the concomitant depressive symptoms in middle-aged individuals with SMCs could reflect structural alterations related to AD.