Paul Malloy

Deep Brain Stimulation of the Ventral Capsule/Ventral Striatum for Treatment-Resistant Depression

BACKGROUND We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. METHODS Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale-24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). RESULTS Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. CONCLUSIONS Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.

Three-Year Outcomes in Deep Brain Stimulation for Highly Resistant Obsessive–Compulsive Disorder

Deep brain stimulation (DBS) of the anterior limb of the internal capsule has been shown to be beneficial in the short term for obsessive–compulsive disorder (OCD) patients who exhaust conventional therapies. Nuttin et al, who published the first DBS for OCD series, found promising results using a capsule target immediately rostral to the anterior commissure extending into adjacent ventral capsule/ventral striatum (VC/VS). Published long-term outcome data are limited to four patients. In this collaborative study, 10 adult OCD patients meeting stringent criteria for severity and treatment resistance had quadripolar stimulating leads implanted bilaterally in the VC/VS. DBS was activated openly 3 weeks later. Eight patients have been followed for at least 36 months. Group Yale-Brown Obsessive Compulsive Scale (YBOCS) scores decreased from 34.6±0.6 (mean±SEM) at baseline (severe) to 22.3±2.1 (moderate) at 36 months (p<0.001). Four of eight patients had a ⩾35% decrease in YBOCS severity at 36 months; in two patients, scores declined between 25 and 35%. Global Assessment of Functioning scores improved from 36.6±1.5 at baseline to 53.8±2.5 at 36 months (p<0.001). Depression and anxiety also improved, as did self-care, independent living, and work, school, and social functioning. Surgical adverse effects included an asymptomatic hemorrhage, a single seizure, and a superficial infection. Psychiatric adverse effects included transient hypomanic symptoms, and worsened depression and OCD when DBS was interrupted by stimulator battery depletion. This open study found promising long-term effects of DBS in highly treatment-resistant OCD.

Deep brain stimulation of the ventral internal capsule/ventral striatum for obsessive-compulsive disorder: worldwide experience

Psychiatric neurosurgery teams in the United States and Europe have studied deep brain stimulation (DBS) of the ventral anterior limb of the internal capsule and adjacent ventral striatum (VC/VS) for severe and highly treatment-resistant obsessive-compulsive disorder. Four groups have collaborated most closely, in small-scale studies, over the past 8 years. First to begin was Leuven/Antwerp, followed by Butler Hospital/Brown Medical School, the Cleveland Clinic and most recently the University of Florida. These centers used comparable patient selection criteria and surgical targeting. Targeting, but not selection, evolved during this period. Here, we present combined long-term results of those studies, which reveal clinically significant symptom reductions and functional improvement in about two-thirds of patients. DBS was well tolerated overall and adverse effects were overwhelmingly transient. Results generally improved for patients implanted more recently, suggesting a ‘learning curve’ both within and across centers. This is well known from the development of DBS for movement disorders. The main factor accounting for these gains appears to be the refinement of the implantation site. Initially, an anterior–posterior location based on anterior capsulotomy lesions was used. In an attempt to improve results, more posterior sites were investigated resulting in the current target, at the junction of the anterior capsule, anterior commissure and posterior ventral striatum. Clinical results suggest that neural networks relevant to therapeutic improvement might be modulated more effectively at a more posterior target. Taken together, these data show that the procedure can be successfully implemented by dedicated interdisciplinary teams, and support its therapeutic promise.

Prediction of functional status from neuropsychological tests in community-dwelling elderly individuals.

Age-related dysfunction of frontal systems can result in deficits in planning, organization, self-control, and awareness of problems, which are likely to affect the ability to care for ones self. The purpose of this study was to determine the relationship between age-related frontal/executive deficits and impairment in instrumental activities of daily living (IADLs) in elderly individuals. Twenty-seven community-dwelling individuals were administered a comprehensive battery of neuropsychological tests and a performance-based evaluation of IADLs. Multiple regression analyses indicated that executive function and depression severity accounted for a significant proportion of variance in IADLs, with executive function making the greatest contribution. Tests measuring other cognitive functions, such as memory, language, and spatial skills, did not contribute significantly to the prediction of functional status. Furthermore, executive measures accounted for more variance than other demographic characteristics such as general health status, age, and educational level. The results of this study indicate that executive dysfunction in normal aging may be the best predictor of functional decline. A better understanding of the mechanisms that underlie IADL skills will ultimately aid in the development of compensatory and intervention strategies designed to delay the onset of assisted living and nursing home placement.

MRI and neuropsychological differences in early- and late-life-onset geriatric depression

We sought to determine whether geriatric patients with late-life-onset major depression have more subcortical hyperintensities on MRI and greater cognitive impairment than age-matched geriatric patients with early-life-onset major depression, suggesting that subcortical disease may be etiologic in late-life depression. Most negative studies of the clinical significance of subcortical hyperintensities on MRI in geriatric patients have sampled from a restricted range of subjects, have employed limited batteries of neuropsychological tests, or have not quantified MRI changes; the present study attempted to address these limitations. Thirty subjects from a geriatric psychiatry inpatient service who were over 60 years of age and presented with major depression were divided into groups with onset of first depression after age 60 (mean = 72.4 years, 15 women, 0 men), and onset of first depression before age 60 (mean = 35.8 years, 12 women, 3 men). Quantitative analysis of MRI yielded the volume of: periventricular hyperintensities (PVH) and deep white-matter hyperintensities (DWMH). Subjects were administered a neuropsychological battery and measures of depression by raters blind to age of onset. The late-onset group had significantly more PVH and DWMH. They were also more impaired on executive and verbal and nonverbal memory tasks. Discriminant function analysis using the severity of subcortical signal hyperintensities on MRI, cognitive index, and depression scores correctly predicted late versus early onset of depression in 87% of the early-onset group and 80% of the late-onset group. These findings suggest that late-life-onset depression may be associated with an increased severity of subcortical vascular disease and greater impairment of cognitive performance. NEUROLOGY 1996;46: 1567-1574

Tests of Executive Function Predict Instrumental Activities of Daily Living in Community-Dwelling Older Individuals

The purpose of this study was to examine the utility of specific tests of executive functioning for predicting instrumental activities of daily living (IADLs) in community-dwelling older individuals (n = 30). In addition to tests of frontal and executive functioning, performance based and caregiver-rated evaluations of IADLs were obtained. Results indicated that different tests of executive functioning were associated with outcomes on performance-based versus caregiver-rated assessments of IADLs. Specifically, the Trail Making Test (Part B) made a significant and unique contribution to the prediction of performance-based IADLs. In contrast, verbal fluency performance and Trail Making Test performance made significant independent contributions to the prediction of IADLs as reported by a caregiver. These findings suggest that different aspects of frontal and executive functions may be related to IADLs, depending on the type of assessment instrument used.

The orbitomedial frontal syndrome.

An orbitomedial frontal syndrome is proposed, characterized by anosmia, amnesia with confabulation, Go-NoGo deficits, personality change, and hypersensitivity to pain. The orbitomedial frontal syndrome is distinct from the clinical picture that results from dorsolateral frontal damage. Aspects of orbitomedial damage have been discussed previously in isolation, but we argue that recognition of this syndrome in toto is clinically important. It appears to be associated with poor social and vocational adjustment after brain injury, and the co-occurrence of features of the syndrome provides clues to underlying mechanisms for disinhibition and confabulation in frontal lobe patients.

Impaired Awareness, Behavior Disturbance, and Caregiver Burden in Alzheimer Disease

Caregiver burden, the stress experienced as a result of caregiving, is determined by many factors. This study examined the contributions of the patients awareness of memory deficit and behavioral disturbance to caregiver burden in Alzheimer disease. Participants were 41 patients with Alzheimer disease and their caregivers. Dementia severity, functional impairment, awareness of memory deficit, and behavioral disturbance were measured and examined in relation to caregiver burden. Positive correlations were found between caregiver burden and both impaired awareness of memory deficit and behavioral disturbance. Regression analyses demonstrated that both impaired patient awareness of memory deficit and behavioral disturbance contributed to caregiver burden over and above dementia severity and functional impairment. However, when both were entered together into regression equations, only behavioral disturbance contributed to caregiver burden. Of the problem behaviors, measures of disinhibition contributed most to caregiver burden. These data further our understanding of the multiple contributors to caregiver burden. We conclude that both patient awareness of memory deficit and behavioral disturbance impact caregiver burden, with behavioral disturbance making the greater contribution.

Factor Analysis of the Frontal Systems Behavior Scale (FrSBe)

The Frontal Systems Behavior Scale (FrSBe), formerly called the Frontal Lobe Personality Scale (FLOPS), is a brief behavior rating scale with demonstrated validity for the assessment of behavior disturbances associated with damage to the frontal-subcortical brain circuits. The authors report an exploratory principal factor analysis of the FrSBe–Family Version in a sample including 324 neurological patients and research participants, of which about 63% were diagnosed with neurodegenerative diseases (Huntingtons, Parkinsons, and Alzheimers diseases). The three-factor solution accounted for a modest level of variance (41%) and confirmed a factor structure consistent with the three subscales proposed on the theoretical basis of the frontal systems. Most items (83%) from the FrSBe subscales of Apathy, Disinhibition, and Executive Dysfunction loaded saliently on three corresponding factors. The FrSBe factor structure supports its utility for assessing both the severity of the three frontal syndromes in aggregate and separately.

A review of rating scales for measuring behavior change due to frontal systems damage

Objective:To perform a critical review of scales designed to measure frontal behavior change. Background:Changes in cognition due to frontal disease or damage have been well described, but noncognitive changes in behavior are often more deleterious functionally for frontal patients. Method:The review concentrates on five behavior rating scales: the Behavior Rating Inventory of Executive Functions (BRIEF), the Dysexecutive Questionnaire (DEX), the Frontal Behavior Inventory (FBI), the Frontal Systems Behavior Scale (FrSBe), the Iowa Rating Scales of Personality Change (IRSPC), and the Neuropsychiatric Inventory (NPI). Other scales purporting to measure specific aspects of frontal functioning, but having less research support, are described briefly. Results and Conclusions:The BRIEF and FrSBe have good reliability and large-scale norms. No norms are available for the other scales. The FrSBe and IRSPC have been shown to be valid in discriminating frontal from nonfrontal lesioned patients, but this has not been shown in the other scales. The FBI and NPI require trained raters, whereas the FrSBe, IRSPC, and BRIEF are administered to patients and/or family informants directly. The NPI and FBI are sensitive to certain changes in behavior attributed to frontal systems disruption but have been used primarily in dementia.