PMC:3839092 / 21306-34233 JSONTXT

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with our hypotheses, analyses revealed reduced WM integrity (i.e., decreased FA, and increased MD, RD, AD) in the MDD group compared to HC as well as in the more severely depressed, anhedonic, and irritable patients. Furthermore, despite significant correlations between the two dimensional measures and depression severity, we found distinct WM alterations for both anhedonia and irritability that differed from those for depression severity. Reduced integrity was found in fronto-striatal and thalamic tracts, the corpus callosum, and tracts connected to the inferior temporal (IT) cortex. Additionally, reduced integrity in the sagittal stratum was consistently found in our analyses to be correlated with increasing depression severity, anhedonia, and irritability. Unexpectedly, analyses also revealed a cluster in the posterior cingulum near the hippocampus which demonstrated more anisotropic diffusion, both as anhedonia increased and in the MDD group vs. HC. Finally, it is interesting to note that in many of our analyses there was overlap in the clusters demonstrating a relationship with FA and RD, potentially suggesting that structural issues related to RD are driving the observed relationships with FA in this and other studies.\n\nGroup differences in WM integrity\nGroup differences were observed in both the posterior and anterior cingulum. Specifically, depressed adolescents demonstrated decreased WM integrity in the anterior cingulum near the precuneus, and increased integrity in the posterior cingulum near the hippocampus, compared to HC. The cingulum connects the cingulate and entorhinal cortices and is broadly involved in attention, memory, and emotions (29, 30). The anterior portion of the cingulate has been implicated in emotional processing and depression (31). Altered functioning, connectivity, and diffusion around the precuneus are frequently reported in MDD (32, 33). Given the role of the precuneus in self-related processes, and that self-processing is typically altered in depression (34), this potentially suggests that reduced WM integrity contributes to altered functioning in this region early in the course of the disease.\nThe MDD group also demonstrated more coherent diffusion in the posterior cingulum near the hippocampus. The posterior cingulate is involved in cognitive functions including attention and memory (35). Functional hyperactivity in the hippocampus (36–38), as well as decreased hippocampal volume (39), are consistent findings in adult MDD. Given the role of the hippocampus in learning and memory (40), but also in the regulation of motivation and emotion (41, 42), this region is critical to carrying out normal behaviors that may be altered in depression. Furthermore, greater WM integrity in tracts leading to the hippocampus would be consistent with the literature demonstrating hyperactivity of this region in non-medicated MDD patients. Overall, the categorical comparison between depressed adolescents and HC revealed differences in an important tract connecting prefrontal and limbic regions.\n\nDepression severity and WM integrity\nOur use of an approach that accounts for a range of depression severity in our sample revealed a pattern of reduced WM integrity as depression severity increased. Specifically, we found reduced integrity in the genu of the corpus callosum, a region that connects prefrontal and orbitofrontal cortices. Many studies have documented altered diffusivity in the genu (16) as well as reduced volume (6, 43–45). Given that the prefrontal and orbitofrontal cortices are involved in critical processes, including decision-making, attention, reward processing, and the evaluation and regulation of emotion (46–48), an interruption in communication between these areas has implications for depression and mood disorders.\nAdditionally, we found decreased integrity in the sagittal stratum with increasing severity, not only in this analysis, but also in the dimensional analyses within the MDD population. The sagittal stratum is a complex fiber bundle connecting the occipital cortex to the rest of the brain, and includes fibers from many major tracts including the ILF and IFOF (49). The ILF and IFOF both connect the occipital cortex to temporal limbic structures (i.e., amygdala, hippocampus) and the PFC, although the IFOF connects directly to the OFC and the ILF does so indirectly through the uncinate fasciculus (50). Therefore, both tracts are involved in connecting visual information with areas involved in emotional memories, judgments, and behaviors. A meta-analysis of diffusion studies of patients with MDD found WM alterations in both the ILF and IFOF (16). Additionally, alterations in WM have been found in the IFOF for depressed adolescents (17), adolescents with a familial risk for depression (18), and adults with MDD (51).\nWe also observed reduced integrity with increasing severity in bilateral clusters in the ATR near the pallidum. The ATR connects thalamic nuclei with the PFC through the anterior limb of the internal capsule. Reduced WM integrity has been reported in the ATR in several studies of depressed adults (16). Furthermore, given the role of the thalamus in motivation and goal pursuit (52, 53), altered connectivity within this circuit could contribute to the motivational deficits associated with depression.\nAdditionally, increased illness severity was associated with reduced integrity in the corticospinal tract near the postcentral gyrus. The corticospinal tract transmits motor impulses from the motor and premotor cortices to the spinal cord. Although this was an unexpected finding, motor disturbances and retardation are a relevant clinical symptom of depression (54). In this way, altered diffusivity may be related to the observed slowing and impairment of motor functions. Finally, we again found decreased integrity with increasing severity in the previously described anterior cingulum near the precuneus, which is consistent with the findings from our group analysis. Overall, our analysis with varied levels of depression severity was more robust than the categorical comparison and revealed a more extensive network of reduced WM integrity.\n\nAnhedonia and WM integrity\nThe dimensional analysis with anhedonia revealed an association between increased anhedonia and reduced integrity in the anterior limb of the internal capsule near the thalamus, a tract implicated in reward processing (19). The anterior limb of the internal capsule connects the thalamus with cingulate and prefrontal cortices, which are heavily involved in motivation, decision-making, and evaluating the saliency of emotional and rewarding stimuli. Additionally, increased anhedonia was correlated with reduced integrity in tracts (i.e., IFOF, projection fibers) connected to the posterior lateral OFC (BA 47), an area involved in many functions including emotional and reward processing, complex learning, and the inhibition of responses (46, 47, 55). Depressed patients have demonstrated reduced gray matter volume in the posterior lateral OFC as well as altered functional responses to emotional stimuli, reward processing, and reversal learning (56).\nWe also found reduced integrity in the external capsule as anhedonia increased. The external capsule contains cholinergic fibers projecting from the basal forebrain to the cerebral cortex. Reduced integrity in the external capsule has been found previously in adult MDD (57, 58). Furthermore, we once again found reduced integrity in the previously discussed sagittal stratum and posterior cingulum near the precuneus with greater symptom severity. Finally, the analysis revealed increased integrity with increased anhedonia in the posterior cingulum near the hippocampus, in an area fairly close to the cluster that showed increased integrity in the MDD group in our categorical comparison. In this way, it is possible that anhedonic symptoms are related to the group differences we observed. Given the previously discussed role of the hippocampus and limbic system in the regulation of motivation and emotion, the relationship between hippocampal functioning and anhedonia represents an important area for future research.\n\nIrritability and WM integrity\nAs predicted, we found decreased integrity as irritability increased in a tract near the amygdala (i.e., sagittal stratum including the ILF and IFOF). However, increased irritability was correlated with decreased integrity in tracts primarily connecting to prefrontal and occipital cortices. We also found clusters in the previously discussed IFOF, although one was in the lingual gyrus while the other was in the middle frontal gyrus. The lingual gyrus has been implicated in processing emotional faces (59), which is typically altered in MDD (60). Altered cerebral blood flow and resting state connectivity have been demonstrated in the lingual gyrus in adults with MDD (61, 62). Additionally, decreased integrity in WM has previously been found around the middle frontal gyrus (63), an area broadly involved in a variety of higher-level cognitive processes (64) which are often compromised in MDD.\nReduced integrity related to elevated irritability was also found in the ACR, which connects the striatum to the ACC. Reduced integrity has previously been demonstrated in the ACR in pediatric bipolar patients (65), and dysfunctional activity in the ACC is typically considered a hallmark of depression (37, 42, 66–70). Furthermore, altered intrinsic functional connectivity (i.e., resting state) between the striatum and ACC has been documented for depressed adolescents (8). Finally, a cluster in the SLF in the IT gyrus was found. The SLF is a major bidirectional association tract connecting large parts of the frontal cortex with the parietal, temporal, and occipital lobes. Less restricted diffusion in the SLF has been previously demonstrated for depressed adolescents (17), adolescents with a genetic risk for depression (18), and adults with MDD (71).\n\nMeasures of WM integrity\nAlthough a complete discussion of RD and AD goes beyond the scope of this paper, it is interesting to note that for both the categorical and dimensional analyses we found overlap in clusters with reduced FA and increased RD, but no overlapping relationships with AD. Increased RD may be caused by disturbances in myelin, whereas decreased AD has been suggested to reflect disrupted axonal integrity (72–74). As such, our findings and those from previous research may reflect that alterations in FA for MDD are being driven more by issues of myelination than axonal integrity. However, further research is needed to replicate and expand upon a possible mechanism.\n\nLimitations and future directions\nAlthough our findings are consistent with other clinical studies investigating altered WM in depressed adolescents, it should be noted that very liberal thresholds were used for the analyses and the inability to correct for multiple comparisons is an issue of concern. Although our statistical methodology and sample size were comparable to those of other studies of clinical populations using DTI (17, 63, 75), it is possible that the sample sizes used in many clinical studies are not large enough to produce adequate statistical power. In this way, it is difficult to adequately balance the concerns of committing a Type I error by not correcting while also avoiding a Type II error due to small sample sizes and reduced statistical power. Therefore, our findings are considered preliminary. Furthermore, the inclusion of patients with milder symptomatology may have weakened our ability to detect group differences.\nAlthough small sample sizes may be a possible explanation for the relatively weak results in our and other clinical studies of adolescent depression, another possibility is that the adolescent brain is still malleable and the alterations in WM structure may not fully take hold until adulthood (11). Therefore, it is even more pressing to understand a neuroimmunological model of depression and the factors that may contribute to changes in WM before chronicity begins to take effect. For example, given past findings that depressed adolescents exhibit higher levels of circulating inflammatory cytokines (76), one possible explanation for the observed reduction in FA in adult MDD is that it may reflect effects of chronic low grade inflammation. Additionally, given our previous research on fronto-striatal functional connectivity in MDD, future studies should investigate altered WM microstructure using a targeted tractography approach. Finally, further research is needed to investigate this hypothesis and other models of the systemic consequences of depression. To this end, a better understanding of what FA, MD, AD, and RD illustrate in an adolescent population, as well as the factors that contribute to these diffusivity measures, is needed in the field.\n"}

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with our hypotheses, analyses revealed reduced WM integrity (i.e., decreased FA, and increased MD, RD, AD) in the MDD group compared to HC as well as in the more severely depressed, anhedonic, and irritable patients. Furthermore, despite significant correlations between the two dimensional measures and depression severity, we found distinct WM alterations for both anhedonia and irritability that differed from those for depression severity. Reduced integrity was found in fronto-striatal and thalamic tracts, the corpus callosum, and tracts connected to the inferior temporal (IT) cortex. Additionally, reduced integrity in the sagittal stratum was consistently found in our analyses to be correlated with increasing depression severity, anhedonia, and irritability. Unexpectedly, analyses also revealed a cluster in the posterior cingulum near the hippocampus which demonstrated more anisotropic diffusion, both as anhedonia increased and in the MDD group vs. HC. Finally, it is interesting to note that in many of our analyses there was overlap in the clusters demonstrating a relationship with FA and RD, potentially suggesting that structural issues related to RD are driving the observed relationships with FA in this and other studies.\n\nGroup differences in WM integrity\nGroup differences were observed in both the posterior and anterior cingulum. Specifically, depressed adolescents demonstrated decreased WM integrity in the anterior cingulum near the precuneus, and increased integrity in the posterior cingulum near the hippocampus, compared to HC. The cingulum connects the cingulate and entorhinal cortices and is broadly involved in attention, memory, and emotions (29, 30). The anterior portion of the cingulate has been implicated in emotional processing and depression (31). Altered functioning, connectivity, and diffusion around the precuneus are frequently reported in MDD (32, 33). Given the role of the precuneus in self-related processes, and that self-processing is typically altered in depression (34), this potentially suggests that reduced WM integrity contributes to altered functioning in this region early in the course of the disease.\nThe MDD group also demonstrated more coherent diffusion in the posterior cingulum near the hippocampus. The posterior cingulate is involved in cognitive functions including attention and memory (35). Functional hyperactivity in the hippocampus (36–38), as well as decreased hippocampal volume (39), are consistent findings in adult MDD. Given the role of the hippocampus in learning and memory (40), but also in the regulation of motivation and emotion (41, 42), this region is critical to carrying out normal behaviors that may be altered in depression. Furthermore, greater WM integrity in tracts leading to the hippocampus would be consistent with the literature demonstrating hyperactivity of this region in non-medicated MDD patients. Overall, the categorical comparison between depressed adolescents and HC revealed differences in an important tract connecting prefrontal and limbic regions.\n\nDepression severity and WM integrity\nOur use of an approach that accounts for a range of depression severity in our sample revealed a pattern of reduced WM integrity as depression severity increased. Specifically, we found reduced integrity in the genu of the corpus callosum, a region that connects prefrontal and orbitofrontal cortices. Many studies have documented altered diffusivity in the genu (16) as well as reduced volume (6, 43–45). Given that the prefrontal and orbitofrontal cortices are involved in critical processes, including decision-making, attention, reward processing, and the evaluation and regulation of emotion (46–48), an interruption in communication between these areas has implications for depression and mood disorders.\nAdditionally, we found decreased integrity in the sagittal stratum with increasing severity, not only in this analysis, but also in the dimensional analyses within the MDD population. The sagittal stratum is a complex fiber bundle connecting the occipital cortex to the rest of the brain, and includes fibers from many major tracts including the ILF and IFOF (49). The ILF and IFOF both connect the occipital cortex to temporal limbic structures (i.e., amygdala, hippocampus) and the PFC, although the IFOF connects directly to the OFC and the ILF does so indirectly through the uncinate fasciculus (50). Therefore, both tracts are involved in connecting visual information with areas involved in emotional memories, judgments, and behaviors. A meta-analysis of diffusion studies of patients with MDD found WM alterations in both the ILF and IFOF (16). Additionally, alterations in WM have been found in the IFOF for depressed adolescents (17), adolescents with a familial risk for depression (18), and adults with MDD (51).\nWe also observed reduced integrity with increasing severity in bilateral clusters in the ATR near the pallidum. The ATR connects thalamic nuclei with the PFC through the anterior limb of the internal capsule. Reduced WM integrity has been reported in the ATR in several studies of depressed adults (16). Furthermore, given the role of the thalamus in motivation and goal pursuit (52, 53), altered connectivity within this circuit could contribute to the motivational deficits associated with depression.\nAdditionally, increased illness severity was associated with reduced integrity in the corticospinal tract near the postcentral gyrus. The corticospinal tract transmits motor impulses from the motor and premotor cortices to the spinal cord. Although this was an unexpected finding, motor disturbances and retardation are a relevant clinical symptom of depression (54). In this way, altered diffusivity may be related to the observed slowing and impairment of motor functions. Finally, we again found decreased integrity with increasing severity in the previously described anterior cingulum near the precuneus, which is consistent with the findings from our group analysis. Overall, our analysis with varied levels of depression severity was more robust than the categorical comparison and revealed a more extensive network of reduced WM integrity.\n\nAnhedonia and WM integrity\nThe dimensional analysis with anhedonia revealed an association between increased anhedonia and reduced integrity in the anterior limb of the internal capsule near the thalamus, a tract implicated in reward processing (19). The anterior limb of the internal capsule connects the thalamus with cingulate and prefrontal cortices, which are heavily involved in motivation, decision-making, and evaluating the saliency of emotional and rewarding stimuli. Additionally, increased anhedonia was correlated with reduced integrity in tracts (i.e., IFOF, projection fibers) connected to the posterior lateral OFC (BA 47), an area involved in many functions including emotional and reward processing, complex learning, and the inhibition of responses (46, 47, 55). Depressed patients have demonstrated reduced gray matter volume in the posterior lateral OFC as well as altered functional responses to emotional stimuli, reward processing, and reversal learning (56).\nWe also found reduced integrity in the external capsule as anhedonia increased. The external capsule contains cholinergic fibers projecting from the basal forebrain to the cerebral cortex. Reduced integrity in the external capsule has been found previously in adult MDD (57, 58). Furthermore, we once again found reduced integrity in the previously discussed sagittal stratum and posterior cingulum near the precuneus with greater symptom severity. Finally, the analysis revealed increased integrity with increased anhedonia in the posterior cingulum near the hippocampus, in an area fairly close to the cluster that showed increased integrity in the MDD group in our categorical comparison. In this way, it is possible that anhedonic symptoms are related to the group differences we observed. Given the previously discussed role of the hippocampus and limbic system in the regulation of motivation and emotion, the relationship between hippocampal functioning and anhedonia represents an important area for future research.\n\nIrritability and WM integrity\nAs predicted, we found decreased integrity as irritability increased in a tract near the amygdala (i.e., sagittal stratum including the ILF and IFOF). However, increased irritability was correlated with decreased integrity in tracts primarily connecting to prefrontal and occipital cortices. We also found clusters in the previously discussed IFOF, although one was in the lingual gyrus while the other was in the middle frontal gyrus. The lingual gyrus has been implicated in processing emotional faces (59), which is typically altered in MDD (60). Altered cerebral blood flow and resting state connectivity have been demonstrated in the lingual gyrus in adults with MDD (61, 62). Additionally, decreased integrity in WM has previously been found around the middle frontal gyrus (63), an area broadly involved in a variety of higher-level cognitive processes (64) which are often compromised in MDD.\nReduced integrity related to elevated irritability was also found in the ACR, which connects the striatum to the ACC. Reduced integrity has previously been demonstrated in the ACR in pediatric bipolar patients (65), and dysfunctional activity in the ACC is typically considered a hallmark of depression (37, 42, 66–70). Furthermore, altered intrinsic functional connectivity (i.e., resting state) between the striatum and ACC has been documented for depressed adolescents (8). Finally, a cluster in the SLF in the IT gyrus was found. The SLF is a major bidirectional association tract connecting large parts of the frontal cortex with the parietal, temporal, and occipital lobes. Less restricted diffusion in the SLF has been previously demonstrated for depressed adolescents (17), adolescents with a genetic risk for depression (18), and adults with MDD (71).\n\nMeasures of WM integrity\nAlthough a complete discussion of RD and AD goes beyond the scope of this paper, it is interesting to note that for both the categorical and dimensional analyses we found overlap in clusters with reduced FA and increased RD, but no overlapping relationships with AD. Increased RD may be caused by disturbances in myelin, whereas decreased AD has been suggested to reflect disrupted axonal integrity (72–74). As such, our findings and those from previous research may reflect that alterations in FA for MDD are being driven more by issues of myelination than axonal integrity. However, further research is needed to replicate and expand upon a possible mechanism.\n\nLimitations and future directions\nAlthough our findings are consistent with other clinical studies investigating altered WM in depressed adolescents, it should be noted that very liberal thresholds were used for the analyses and the inability to correct for multiple comparisons is an issue of concern. Although our statistical methodology and sample size were comparable to those of other studies of clinical populations using DTI (17, 63, 75), it is possible that the sample sizes used in many clinical studies are not large enough to produce adequate statistical power. In this way, it is difficult to adequately balance the concerns of committing a Type I error by not correcting while also avoiding a Type II error due to small sample sizes and reduced statistical power. Therefore, our findings are considered preliminary. Furthermore, the inclusion of patients with milder symptomatology may have weakened our ability to detect group differences.\nAlthough small sample sizes may be a possible explanation for the relatively weak results in our and other clinical studies of adolescent depression, another possibility is that the adolescent brain is still malleable and the alterations in WM structure may not fully take hold until adulthood (11). Therefore, it is even more pressing to understand a neuroimmunological model of depression and the factors that may contribute to changes in WM before chronicity begins to take effect. For example, given past findings that depressed adolescents exhibit higher levels of circulating inflammatory cytokines (76), one possible explanation for the observed reduction in FA in adult MDD is that it may reflect effects of chronic low grade inflammation. Additionally, given our previous research on fronto-striatal functional connectivity in MDD, future studies should investigate altered WM microstructure using a targeted tractography approach. Finally, further research is needed to investigate this hypothesis and other models of the systemic consequences of depression. To this end, a better understanding of what FA, MD, AD, and RD illustrate in an adolescent population, as well as the factors that contribute to these diffusivity measures, is needed in the field.\n"}