Gretchen O. Reynolds

Predicting treatment response in social anxiety disorder from functional magnetic resonance imaging.

CONTEXT Current behavioral measures poorly predict treatment outcome in social anxiety disorder (SAD). To our knowledge, this is the first study to examine neuroimaging-based treatment prediction in SAD. OBJECTIVE To measure brain activation in patients with SAD as a biomarker to predict subsequent response to cognitive behavioral therapy (CBT). DESIGN Functional magnetic resonance imaging (fMRI) data were collected prior to CBT intervention. Changes in clinical status were regressed on brain responses and tested for selectivity for social stimuli. SETTING Patients were treated with protocol-based CBT at anxiety disorder programs at Boston University or Massachusetts General Hospital and underwent neuroimaging data collection at Massachusetts Institute of Technology. PATIENTS Thirty-nine medication-free patients meeting DSM-IV criteria for the generalized subtype of SAD. INTERVENTIONS Brain responses to angry vs neutral faces or emotional vs neutral scenes were examined with fMRI prior to initiation of CBT. MAIN OUTCOME MEASURES Whole-brain regression analyses with differential fMRI responses for angry vs neutral faces and changes in Liebowitz Social Anxiety Scale score as the treatment outcome measure. RESULTS Pretreatment responses significantly predicted subsequent treatment outcome of patients selectively for social stimuli and particularly in regions of higher-order visual cortex. Combining the brain measures with information on clinical severity accounted for more than 40% of the variance in treatment response and substantially exceeded predictions based on clinical measures at baseline. Prediction success was unaffected by testing for potential confounding factors such as depression severity at baseline. CONCLUSIONS The results suggest that brain imaging can provide biomarkers that substantially improve predictions for the success of cognitive behavioral interventions and more generally suggest that such biomarkers may offer evidence-based, personalized medicine approaches for optimally selecting among treatment options for a patient.

Failure of Working Memory Training to Enhance Cognition or Intelligence

Fluid intelligence is important for successful functioning in the modern world, but much evidence suggests that fluid intelligence is largely immutable after childhood. Recently, however, researchers have reported gains in fluid intelligence after multiple sessions of adaptive working memory training in adults. The current study attempted to replicate and expand those results by administering a broad assessment of cognitive abilities and personality traits to young adults who underwent 20 sessions of an adaptive dual n-back working memory training program and comparing their post-training performance on those tests to a matched set of young adults who underwent 20 sessions of an adaptive attentional tracking program. Pre- and post-training measurements of fluid intelligence, standardized intelligence tests, speed of processing, reading skills, and other tests of working memory were assessed. Both training groups exhibited substantial and specific improvements on the trained tasks that persisted for at least 6 months post-training, but no transfer of improvement was observed to any of the non-trained measurements when compared to a third untrained group serving as a passive control. These findings fail to support the idea that adaptive working memory training in healthy young adults enhances working memory capacity in non-trained tasks, fluid intelligence, or other measures of cognitive abilities.

Brain connectomics predict response to treatment in social anxiety disorder

We asked whether brain connectomics can predict response to treatment for a neuropsychiatric disorder better than conventional clinical measures. Pre-treatment resting-state brain functional connectivity and diffusion-weighted structural connectivity were measured in 38 patients with social anxiety disorder (SAD) to predict subsequent treatment response to cognitive behavioral therapy (CBT). We used a priori bilateral anatomical amygdala seed-driven resting connectivity and probabilistic tractography of the right inferior longitudinal fasciculus together with a data-driven multivoxel pattern analysis of whole-brain resting-state connectivity before treatment to predict improvement in social anxiety after CBT. Each connectomic measure improved the prediction of individuals’ treatment outcomes significantly better than a clinical measure of initial severity, and combining the multimodal connectomics yielded a fivefold improvement in predicting treatment response. Generalization of the findings was supported by leave-one-out cross-validation. After dividing patients into better or worse responders, logistic regression of connectomic predictors and initial severity combined with leave-one-out cross-validation yielded a categorical prediction of clinical improvement with 81% accuracy, 84% sensitivity and 78% specificity. Connectomics of the human brain, measured by widely available imaging methods, may provide brain-based biomarkers (neuromarkers) supporting precision medicine that better guide patients with neuropsychiatric diseases to optimal available treatments, and thus translate basic neuroimaging into medical practice.

The Therapeutic Potential of Exercise to Improve Mood, Cognition, and Sleep in Parkinson's Disease

In addition to the classic motor symptoms, Parkinsons disease (PD) is associated with a variety of nonmotor symptoms that significantly reduce quality of life, even in the early stages of the disease. There is an urgent need to develop evidence‐based treatments for these symptoms, which include mood disturbances, cognitive dysfunction, and sleep disruption. We focus here on exercise interventions, which have been used to improve mood, cognition, and sleep in healthy older adults and clinical populations, but to date have primarily targeted motor symptoms in PD. We synthesize the existing literature on the benefits of aerobic exercise and strength training on mood, sleep, and cognition as demonstrated in healthy older adults and adults with PD, and suggest that these types of exercise offer a feasible and promising adjunct treatment for mood, cognition, and sleep difficulties in PD. Across stages of the disease, exercise interventions represent a treatment strategy with the unique ability to improve a range of nonmotor symptoms while also alleviating the classic motor symptoms of the disease. Future research in PD should include nonmotor outcomes in exercise trials with the goal of developing evidence‐based exercise interventions as a safe, broad‐spectrum treatment approach to improve mood, cognition, and sleep for individuals with PD.

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.

Side and Type of Initial Motor Symptom Influences Visuospatial Functioning in Parkinson's Disease

BACKGROUND/OBJECTIVES Visuospatial problems are common in Parkinsons disease (PD) and likely stem from dysfunction in dopaminergic pathways and consequent disruption of cortical functioning. Characterizing the motor symptoms at disease onset provides a method of observing how dysfunction in these pathways influences visuospatial cognition. We examined two types of motor characteristics: Body side (left or right) and type of initial symptom (tremor or symptom other than tremor). METHODS 31 non-demented patients with PD, 16 with left-side onset (LPD) and 15 with right-side onset (RPD), as well as 17 healthy control participants (HC). The PD group was also divided by type of initial motor symptom, 15 having tremor as the initial symptom and 16 having an initial symptom other than tremor. Visuospatial function was assessed with the Clock Drawing Test. RESULTS Of the four Clock Drawing scoring methods used, the Rouleau method showed sensitivity to subgroup differences. As predicted, the LPD and non-tremor subgroups, but not the other subgroups, performed more poorly than the HC group. CONCLUSION The findings provide further evidence for differences in cognition between these subtypes of PD and highlight the importance of considering disease subtypes when examining cognition.

Visuospatial Attention to Single and Multiple Objects Is Independently Impaired in Parkinson's Disease

Parkinson’s disease (PD) is associated with deficits in visuospatial attention. It is as yet unknown whether these attentional deficits begin at a perceptual level or instead reflect disruptions in oculomotor or higher-order processes. In the present study, non-demented individuals with PD and matched normal control adults (NC) participated in two tasks requiring sustained visuospatial attention, both based on a multiple object tracking paradigm. Eye tracking was used to ensure central fixation. In Experiment 1 (26 PD, 21 NC), a pair of identical red dots (one target, one distractor) rotated randomly for three seconds at varied speeds. The task was to maintain the identity of the sole target, which was labeled prior to each trial. PD were less accurate than NC overall (p = .049). When considering only trials where fixation was maintained, however, there was no significant group difference, suggesting that the deficit’s origin is closely related to oculomotor processing. To determine whether PD had additional impairment in multifocal attention, in Experiment 2 (25 PD, 15 NC), two targets were presented along with distractors at a moderate speed, along with a control condition in which dots remained stationary. PD were less accurate than NC for moving (p = 0.02) but not stationary targets. This group difference remained significant when considering only trials where fixation was maintained, suggesting the source of the PD deficit was independent from oculomotor processing. Taken together, the results implicate separate mechanisms for single vs. multiple object tracking deficits in PD.

The Relation of Anxiety and Cognition in Parkinson’s Disease.

Objective: Parkinson’s disease (PD) has long been conceptualized as a motor disorder, but nonmotor symptoms also manifest in the disease and significantly reduce quality of life. Anxiety and cognitive dysfunction are prevalent nonmotor symptoms, even in early disease stages, but the relation between these symptoms remains poorly understood. We examined self-reported anxiety and neurocognitive function, indexed by measures of executive function (set-shifting and phonemic fluency), categorical fluency, and attention/working memory. We hypothesized that anxiety would correlate with cognitive performance. Method: The Beck Anxiety Inventory and cognitive tests (Trail Making, Verbal Fluency, Digit Span) were administered to 77 nondemented adults with mild to moderate idiopathic PD (39 men, 38 women; Mage = 62.9 years). Results: Higher anxiety was associated with more advanced disease stage and severity and with poorer set-shifting when using a derived metric to account for motoric slowing. Depression correlated with greater anxiety and disease severity, but not with cognitive performance. Conclusions: Our findings support the association of anxiety with a specific domain of executive function, set-shifting, in nondemented individuals with mild to moderate PD, raising the possibility that treatment of anxiety may alleviate aspects of executive dysfunction in this population.