Desmond J. Oathes

Identification of a Common Neurobiological Substrate for Mental Illness

IMPORTANCEnPsychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness.nnnOBJECTIVEnTo conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis.nnnDATA SOURCESnPubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data.nnnDATA EXTRACTION AND SYNTHESISnStudies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach.nnnMAIN OUTCOMES AND MEASURESnWe tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition.nnnRESULTSnBased on the voxel-based morphometry meta-analysis of 193 studies comprising 15u2009892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning.nnnCONCLUSIONS AND REVELANCEnWe identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.

Anticipatory Activation in the Amygdala and Anterior Cingulate in Generalized Anxiety Disorder and Prediction of Treatment Response

OBJECTIVEnThe anticipation of adverse outcomes, or worry, is a cardinal symptom of generalized anxiety disorder. Prior work with healthy subjects has shown that anticipating aversive events recruits a network of brain regions, including the amygdala and anterior cingulate cortex. This study tested whether patients with generalized anxiety disorder have alterations in anticipatory amygdala function and whether anticipatory activity in the anterior cingulate cortex predicts treatment response.nnnMETHODnFunctional magnetic resonance imaging (fMRI) was employed with 14 generalized anxiety disorder patients and 12 healthy comparison subjects matched for age, sex, and education. The event-related fMRI paradigm was composed of one warning cue that preceded aversive pictures and a second cue that preceded neutral pictures. Following the fMRI session, patients received 8 weeks of treatment with extended-release venlafaxine.nnnRESULTSnPatients with generalized anxiety disorder showed greater anticipatory activity than healthy comparison subjects in the bilateral dorsal amygdala preceding both aversive and neutral pictures. Building on prior reports of pretreatment anterior cingulate cortex activity predicting treatment response, anticipatory activity in that area was associated with clinical outcome 8 weeks later following treatment with venlafaxine. Higher levels of pretreatment anterior cingulate cortex activity in anticipation of both aversive and neutral pictures were associated with greater reductions in anxiety and worry symptoms.nnnCONCLUSIONSnThese findings of heightened and indiscriminate amygdala responses to anticipatory signals in generalized anxiety disorder and of anterior cingulate cortex associations with treatment response provide neurobiological support for the role of anticipatory processes in the pathophysiology of generalized anxiety disorder.

Resting-state connectivity biomarkers define neurophysiological subtypes of depression

Biomarkers have transformed modern medicine but remain largely elusive in psychiatry, partly because there is a weak correspondence between diagnostic labels and their neurobiological substrates. Like other neuropsychiatric disorders, depression is not a unitary disease, but rather a heterogeneous syndrome that encompasses varied, co-occurring symptoms and divergent responses to treatment. By using functional magnetic resonance imaging (fMRI) in a large multisite sample (n = 1,188), we show here that patients with depression can be subdivided into four neurophysiological subtypes (biotypes) defined by distinct patterns of dysfunctional connectivity in limbic and frontostriatal networks. Clustering patients on this basis enabled the development of diagnostic classifiers (biomarkers) with high (82–93%) sensitivity and specificity for depression subtypes in multisite validation (n = 711) and out-of-sample replication (n = 477) data sets. These biotypes cannot be differentiated solely on the basis of clinical features, but they are associated with differing clinical-symptom profiles. They also predict responsiveness to transcranial magnetic stimulation therapy (n = 154). Our results define novel subtypes of depression that transcend current diagnostic boundaries and may be useful for identifying the individuals who are most likely to benefit from targeted neurostimulation therapies.

Causal interactions between fronto-parietal central executive and default-mode networks in humans

Significance Three large-scale neural networks are thought to play important roles in cognitive and emotional information processing in humans. It has been theorized that the “central executive” and “salience” networks achieve this by regulating the “default mode” network. Support for this idea comes from correlational neuroimaging studies; however, direct evidence for this neural mechanism is lacking. We tested this hypothesized mechanism by exciting or inhibiting nodes within the central executive and salience networks using noninvasive brain stimulation and observed the results using simultaneous brain imaging. We found that the default mode network is under inhibitory control specifically from a node in the central executive network, which provides mechanistic insights into prior work that implicates these networks in a range of neuropsychiatric disorders. Information processing during human cognitive and emotional operations is thought to involve the dynamic interplay of several large-scale neural networks, including the fronto-parietal central executive network (CEN), cingulo-opercular salience network (SN), and the medial prefrontal-medial parietal default mode networks (DMN). It has been theorized that there is a causal neural mechanism by which the CEN/SN negatively regulate the DMN. Support for this idea has come from correlational neuroimaging studies; however, direct evidence for this neural mechanism is lacking. Here we undertook a direct test of this mechanism by combining transcranial magnetic stimulation (TMS) with functional MRI to causally excite or inhibit TMS-accessible prefrontal nodes within the CEN or SN and determine consequent effects on the DMN. Single-pulse excitatory stimulations delivered to only the CEN node induced negative DMN connectivity with the CEN and SN, consistent with the CEN/SN’s hypothesized negative regulation of the DMN. Conversely, low-frequency inhibitory repetitive TMS to the CEN node resulted in a shift of DMN signal from its normally low-frequency range to a higher frequency, suggesting disinhibition of DMN activity. Moreover, the CEN node exhibited this causal regulatory relationship primarily with the medial prefrontal portion of the DMN. These findings significantly advance our understanding of the causal mechanisms by which major brain networks normally coordinate information processing. Given that poorly regulated information processing is a hallmark of most neuropsychiatric disorders, these findings provide a foundation for ways to study network dysregulation and develop brain stimulation treatments for these disorders.

Reduced Structural Connectivity of a Major Frontolimbic Pathway in Generalized Anxiety Disorder

CONTEXTnEmotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD.nnnOBJECTIVESnTo investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas.nnnDESIGNnParticipants underwent diffusion-tensor imaging and functional magnetic resonance imaging.nnnSETTINGnUniversity magnetic resonance imaging facility.nnnPARTICIPANTSnForty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education.nnnMAIN OUTCOME MEASURESnThe mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data.nnnRESULTSnLower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion.nnnCONCLUSIONSnReduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.

Dissecting the Anticipation of Aversion Reveals Dissociable Neural Networks

The anticipation of future adversity confers adaptive benefits by engaging a suite of preparatory mechanisms, but this process can also be deleterious when carried out in excess. Neuroscientific investigations have largely treated anticipation as a unitary process, but we show here using functional magnetic resonance imaging that distinct stages of aversive anticipation are supported by dissociable neural mechanisms. Immediate anticipatory responses were observed in regions associated with threat detection and early processing of predictive cues, including the orbitofrontal cortex and pregenual anterior cingulate cortex, as well as the amygdala for individuals with elevated anxiety symptoms. Sustained anticipatory activity was observed in the forebrain/bed nucleus of the stria terminalis, anterior insula, anterior mid-cingulate cortex (aMCC), and midbrain/periaqueductal gray, regions associated with anxiety, interoception, and defensive behavior. The aMCC showed increased functional coupling with the midbrain during sustained anticipation of aversion, highlighting a circuit critical for the expression of preparatory fear responses. These data implicate distinct sets of regions that are active during different temporal stages of anticipation, and provide insight into how the human brain faces the future both adaptively and maladaptively.

Worry, Generalized Anxiety Disorder, and Emotion: Evidence from the EEG Gamma Band

The present study examined EEG gamma (35-70 Hz) spectral power distributions during worry inductions in participants suffering from generalized anxiety disorder (GAD) and in control participants without a history of psychiatric illness. As hypothesized, the EEG gamma band was useful for differentiating worry from baseline and relaxation. During worry induction, GAD patients showed higher levels of gamma activity than control participants in posterior electrode sites that have been previously associated with negative emotion. Gamma fluctuations in these electrode sites were correlated with subjective emotional experience ratings lending additional support to interpretations of negative affect. Following 14 weeks of psychotherapy, the GAD group reported less negative affect with worry inductions and the corresponding gamma sites that previously differentiated the clinical from control groups changed for the GAD patients in the direction of control participants. These findings suggest converging evidence that patients suffering from GAD experience more negative emotion during worry and that the EEG gamma band is useful for monitoring fluctuations in pathological worry expected to follow successful treatment.

Neurobiological Signatures of Anxiety and Depression in Resting-State Functional Magnetic Resonance Imaging

BACKGROUNDnThere is increasing interest in using neurobiological measures to inform psychiatric nosology. It is unclear at the present time whether anxiety and depression are neurobiologically distinct or similar processes. It is also unknown if the best way to examine these disorders neurobiologically is by contrasting categorical definitions or by examining symptom dimensions.nnnMETHODSnA cross-sectional neuroimaging study was conducted of patients with generalized anxiety disorder (GAD), major depressive disorder (MDD), comorbid GAD and MDD (GAD/MDD), or neither GAD nor MDD (control subjects). There were 90 participants, all medication-free (17 GAD, 12 MDD, 23 GAD/MDD, and 38 control subjects). Diagnosis/category and dimensions/symptoms were assessed to determine the best fit for neurobiological data. Symptoms included general distress, common to anxiety and depression, and anxiety-specific (anxious arousal) or depression-specific (anhedonia) symptoms. Low-frequency (.008-.1 Hz) signal amplitude and functional connectivity analyses of resting-state functional magnetic resonance imaging data focused on a priori cortical and subcortical regions of interest.nnnRESULTSnSupport was found for effects of diagnosis above and beyond effects related to symptom levels as well as for effects of symptom levels above and beyond effects of diagnostic categories. The specific dimensional factors of general distress and anxious arousal as well as a diagnosis of MDD explained unique proportions of variance in signal amplitude or functional connectivity.nnnCONCLUSIONSnUsing resting-state functional magnetic resonance imaging, our data show that a single conceptual model alone (i.e., categorical diagnoses or symptom dimensions) provides an incomplete mapping of psychopathology to neurobiology. Instead, the data support an additive model that best captures abnormal neural patterns in patients with anxiety and depression.

Dissociative Tendencies and Facilitated Emotional Processing

Dissociation is a process linked to lapses of attention, history of abuse or trauma, compromised emotional memory, and a disintegrated sense of self. It is theorized that dissociation stems from avoiding emotional information, especially negative emotion, to protect a fragile psyche. The present study tested whether or not dissociaters do actually avoid processing emotion by asking groups scoring high or low on the Dissociative Experiences Scale to judge the affective valence of several types of emotional stimuli. Manipulations of valence, modality (pictures or words), task complexity, and personal relevance lead to results suggesting that dissociation is linked to facilitated rather than deficient emotional processing. Our results are consistent with a theory that sensitivity to emotional material may be a contributing factor in subsequent dissociation to avoid further elaboration of upsetting emotion in these individuals. The findings for dissociation further exemplify the influence of individual differences in the link between cognition and emotion.

Worry facilitates corticospinal motor response to transcranial magnetic stimulation

Like other forms of emotion, anxiety has been theoretically linked to preparation for action. Worry is a type of anticipatory anxiety and the hallmark of generalized anxiety disorder. Research has shown that worry is associated with vigilance to threat cues and increased muscle tension, which may in part be explained by motor facilitation that accompanies preparation for action. This study assessed corticospinal motor responses during worry using transcranial magnetic stimulation (TMS). Participants received TMS during a worry induction, during motor imagery, and during mental arithmetic, while electromyography and force were measured. TMS over the primary motor cortex elicited larger corticospinal motor responses during worry than mental arithmetic and smaller responses than motor imagery of maximum voluntary contraction of targeted muscles. These findings suggest that the association between worry and motor preparation cannot be explained by high cognitive load and provide further support for theoretical accounts emphasizing the role of action preparation in anxiety. Depression and Anxiety, 2008.