Patient-specific connectomic models correlate with, but do not reliably predict, outcomes in deep brain stimulation for obsessive-compulsive disorder.

Deep brain stimulation (DBS) of the ventral internal capsule/ventral striatum (VCVS) is an emerging treatment for obsessive-compulsive disorder (OCD). Recently, multiple studies using normative connectomes have correlated DBS outcomes to stimulation of specific white matter tracts. Those studies did not test whether these correlations are clinically predictive, and did not apply cross-validation approaches that are necessary for biomarker development. Further, they did not account for the possibility of systematic differences between DBS patients and the non-diagnosed controls used in normative connectomes. To address these gaps, we performed patient-specific diffusion imaging in 8 patients who underwent VCVS DBS for OCD. We delineated tracts connecting thalamus and subthalamic nucleus (STN) to prefrontal cortex via VCVS. We then calculated which tracts were likely activated by individual patients' DBS settings. We fit multiple statistical models to predict both OCD and depression outcomes from tract activation. We further attempted to predict hypomania, a VCVS DBS complication. We assessed all models' performance on held-out test sets. With this best-practices approach, no model predicted OCD response, depression response, or hypomania above chance. Coefficient inspection partly supported prior reports, in that capture of tracts projecting to cingulate cortex was associated with both YBOCS and MADRS response. In contrast to prior reports, however, tracts connected to STN were not reliably correlated with response. Thus, patient-specific imaging and a guideline-adherent analysis were unable to identify a tractographic target with sufficient effect size to drive clinical decision-making or predict individual outcomes. These findings suggest caution in interpreting the results of normative connectome studies.

Case Report of Dual-Site Neurostimulation and Chronic Recording of Cortico-Striatal Circuitry in a Patient With Treatment Refractory Obsessive Compulsive Disorder.

Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+ S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.

Neural correlates of the ADHD self-report scale.

BACKGROUND: The ADHD Self Report Scale is a self-report measure that assesses attentional problems. We sought to validate the ASRS by establishing neural correlates using functional magnetic imaging in healthy controls and individuals with bipolar disorder (BD), who commonly exhibit attentional problems. METHODS: ASRS questionnaires and functional MRI data in conjunction with the Multi-source Interference Task (MSIT) were collected from 36 healthy control and 36 BD participants. We investigated task specific changes in the dorsal anterior cingulate cortex (dACC, Brodmann area 32) and their correlations with ASRS subscale scores, inattention and hyperactivity, in both cohorts. RESULTS: As hypothesized, the dACC showed significant increases in BOLD activation between the interference and noninterference conditions. For the ASRS scale as well as its Inattention and Hyperactivity subscales, there was a significant negative correlation with the dACC BOLD for the whole group. CONCLUSIONS: The ASRS is sensitive to attentional difficulties in BD, suggesting that it is a valid tool for assessing attentional difficulties in patients with BD.

The latency of a visual evoked potential tracks the onset of decision making.

Encoding of a sensory stimulus is believed to be the first step in perceptual decision making. Previous research has shown that electrical signals recorded from the human brain track evidence accumulation during perceptual decision making (Gold and Shadlen, 2007; O'Connell et al., 2012; Philiastides et al., 2014). In this study we directly tested the hypothesis that the latency of the N200 recorded by EEG (a negative peak occurring between 150 and 275 ms after stimulus presentation in human participants) reflects the visual encoding time (VET) required for completion of figure-ground segregation before evidence accumulation. We show that N200 latencies vary across individuals, are modulated by external visual noise, and increase response time by x milliseconds when they increase by x milliseconds, reflecting a linear regression slope of 1. Simulations of cognitive decision-making theory show that variation in human response times not related to evidence accumulation (non-decision time; NDT), including VET, are tracked by the fastest response times. Evidence that VET is tracked by N200 latencies was found by fitting a linear model between trial-averaged N200 latencies and the 10th percentiles of response times, a model-independent estimate of NDT. Fitting a novel neuro-cognitive model of decision making also yielded a slope of 1 between N200 latency and model-estimated NDT in multiple visual noise conditions, indicating that N200 latencies track the completion of visual encoding and the onset of evidence accumulation. The N200 waveforms were localized to the cortical surface at distributed temporal and extrastriate locations, consistent with a distributed network engaged in figure-ground segregation of the target stimulus.

Deficits in frontoparietal activation and anterior insula functional connectivity during regulation of cognitive-affective interference in bipolar disorder.

OBJECTIVES: Bipolar disorders (BD) are characterized by emotion and cognitive dysregulation. Mapping deficits in the neurocircuitry of cognitive-affective regulation allows for potential identification of intervention targets. This study used functional MRI data in BD patients and healthy controls during performance on a task requiring cognitive and inhibitory control superimposed on affective images, assessing cognitive and affective interference. METHODS: Functional MRI data were collected from 39 BD patients and 36 healthy controls during performance on the Multi-Source Interference Task overlaid on images from the International Affective Picture System (MSIT-IAPS). Analyses examined patterns of activation in a priori regions implicated in cognitive and emotional processing. Functional connectivity to the anterior insula during task performance was also examined, given this region's role in emotion-cognition integration. RESULTS: BD patients showed significantly less activation during cognitive interference trials in inferior parietal lobule, dorsomedial prefrontal cortex, anterior insula, mid-cingulate, and ventrolateral prefrontal cortex regardless of affective valence. BD patients showed deviations in functional connectivity with anterior insula in regions of the default mode and frontoparietal control networks during negatively valenced cognitive interference trials. CONCLUSIONS: Our findings show disruptions in cognitive regulation and inhibitory control in BD patients in the presence of irrelevant affective distractors. Results of this study suggest one pathway to dysregulation in BD is through inefficient integration of affective and cognitive information, and highlight the importance of developing interventions that target emotion-cognition integration in BD.

Deep Brain Stimulation in Psychiatry: Mechanisms, Models, and Next-Generation Therapies.

Deep brain stimulation has preliminary evidence of clinical efficacy, but has been difficult to develop into a robust therapy, in part because its mechanisms are incompletely understood. We review evidence from movement and psychiatric disorder studies, with an emphasis on how deep brain stimulation changes brain networks. From this, we argue for a network-oriented approach to future deep brain stimulation studies. That network approach requires methods for identifying patients with specific circuit/network deficits. We describe how dimensional approaches to diagnoses may aid that identification. We discuss the use of network/circuit biomarkers to develop self-adjusting "closed loop" systems.

Intrinsic functional neurocircuitry associated with treatment response to transdiagnostic CBT in bipolar disorder with anxiety.

BACKGROUND: Anxiety in bipolar disorder (BD) exacerbates emotion dysregulation and reduces treatment response. We recently conducted a pilot trial of transdiagnostic CBT to target anxiety and emotion dysregulation in BD adjunctive to pharmacotherapy. Reductions in depression and anxiety symptoms were significantly predicted by baseline levels of neuroticism and perceived affective control, as well as changes over time in emotion regulation skills. The present study investigates mechanism of treatment response by examining the relationship between baseline emotion regulation-related neural circuitry and trial outcomes. METHODS: Nineteen patients completed baseline resting state fMRI scans prior to treatment randomization. Functional connectivity between the anterior insula (AI) and regions in the salience network (SN), default mode network (DMN), and executive control network (ECN) were examined as predictors of baseline and treatment-related changes in emotion regulation. RESULTS: Greater improvements in emotion regulation were predicted by weaker right dorsal AI - right ventrolateral prefrontal cortex (VLPFC; SN) and stronger bilateral dorsal AI - bilateral amygdala functional connectivity. Baseline neuroticism was negatively correlated with right dorsal AI- inferior parietal lobule (ECN) functional connectivity, and baseline deficits in perceived affective control were positively associated with ventral AI - bilateral dACC (SN) connectivity. LIMITATIONS: Small sample limits interpretability of treatment-specific effects. CONCLUSION: Baseline functional connectivity of emotion-regulation related neural circuitry significantly predicted change in emotion regulation-related dimensions associated with anxiety and depression symptom reduction. Future studies are needed to determine if employing methods such as neuromodulation to rehabilitate relevant neural circuitry may improve ultimate treatment outcomes of transdiagnostic CBT for BD and anxiety.

Ketamine-Associated Brain Changes: A Review of the Neuroimaging Literature.

Major depressive disorder (MDD) is one of the most prevalent conditions in psychiatry. Patients who do not respond to traditional monoaminergic antidepressant treatments have an especially difficult-to-treat type of MDD termed treatment-resistant depression. Subanesthetic doses of ketamine-a glutamatergic modulator-have shown great promise for rapidly treating patients with the most severe forms of depression. As such, ketamine represents a promising probe for understanding the pathophysiology of depression and treatment response. Through neuroimaging, ketamine's mechanism may be elucidated in humans. Here, we review 47 articles of ketamine's effects as revealed by neuroimaging studies. Some important brain areas emerge, especially the subgenual anterior cingulate cortex. Furthermore, ketamine may decrease the ability to self-monitor, may increase emotional blunting, and may increase activity in reward processing. Further studies are needed, however, to elucidate ketamine's mechanism of antidepressant action.

Memory performance predicts response to psychotherapy for depression in bipolar disorder: A pilot randomized controlled trial with exploratory functional magnetic resonance imaging.

OBJECTIVE: This pilot randomized controlled trial compared Cognitive Behavior Therapy (CBT) and Supportive Psychotherapy (SP) for the treatment of depression in bipolar I disorder. We also examined whether exploratory verbal memory, executive functioning, and neural correlates of verbal memory during functional magnetic resonance imaging (fMRI) predicted change in depression severity. METHODS: Thirty-two adults (ages 18-65) with DSM-IV bipolar I disorder meeting current criteria for a major depressive episode were randomized to 18 weeks of CBT or SP. Symptom severity was assessed before, at the mid-point, and after the 18-week intervention. All participants completed a brief pre-treatment neuropsychological testing battery (including the California Verbal Learning Test-2nd Edition, Delis Kaplan Executive Functioning System [DKEFS] Trail-making Test, and DKEFS Sorting Test), and a sub-set of 17 participants provided usable fMRI data while completing a verbal learning paradigm that consisted of encoding word lists. RESULTS: CBT and SP yielded comparable improvement in depressive symptoms from pre- to post-treatment. Better retention of learned information (CVLT-II long delay free recall vs. Trial 5) and recognition (CVLT-II hits) were associated with greater improvement in depression in both treatments. Increased activation in the left dorsolateral prefrontal cortex and right hippocampus during encoding was also related to depressive symptom improvement. LIMITATIONS: Sample size precluded tests of clinical factors that may interact with cognitive/neural function to predict treatment outcome. CONCLUSION: Neuropsychological assessment and fMRI offer additive information regarding who is most likely to benefit from psychotherapy for bipolar depression.