Keith S. Garcia

Cognitive Function in Late Life Depression: Relationships to Depression Severity, Cerebrovascular Risk Factors and Processing Speed

BACKGROUND A number of studies have examined clinical factors linked to worse neuropsychological performance in late life depression (LLD). To understand the influence of LLD on cognition, it is important to determine if deficits in a number of cognitive domains are relatively independent, or mediated by depression- related deficits in a basic domain such as processing speed. METHODS Patients who met DSM-IV criteria for major depression (n = 155) were administered a comprehensive neuropsychological battery of tasks grouped into episodic memory, language, working memory, executive function, and processing speed domains. Multiple regression analyses were conducted to determine contributions of predictor variables to cognitive domains. RESULTS Age, depression severity, education, race and vascular risk factors all made significant and independent contributions to one or more domains of cognitive function, with all five making independent contributions to processing speed. Age of onset made no independent contribution, after accounting for age and vascular risk factors. Of the five cognitive domains investigated, changes in processing speed were found to most fully mediate the influence of predictor variables on all other cognitive domains. CONCLUSIONS While slowed processing speed appears to be the most core cognitive deficit in LLD, it was closely followed by executive function as a core cognitive deficit. Future research is needed to help clarify mechanisms leading to LLD- related changes in processing speed, including the potential role of white matter abnormalities.

Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses

Contradictory results have been reported regarding the effects of cerebellar cortex lesions on the expression of conditioned eyelid responses--either no effect, partial to complete abolition of responses, or disruption of response timing. This uncertainty is increased by debates regarding the region(s) of cerebellar cortex that are involved, by the likelihood that cortex lesions can inadvertently include damage to the interpositus nucleus or other pathways necessary for response expression, and by potential confounds from the degeneration of climbing fibers produced by cerebellar cortex lesions. We have addressed these issues by reversibly blocking cerebellar cortex output via infusion of the GABA antagonist picrotoxin into the interpositus nucleus. After picrotoxin infusion, conditioned responses are spared but their timing is disrupted and their amplitude diminished. In the same animals, conditioned responses were abolished by infusion of the GABA agonist muscimol and were unaffected by infusion of saline vehicle. These results are consistent with the hypothesis that (i) plasticity in the interpositus nucleus contributes to the expression of conditioned responses, as suggested by the responses seen with the cortex disconnected, and (ii) plasticity in the cerebellar cortex also contributes to conditioned response expression, as suggested by disruption of response timing.

Effect of concomitant pharmacotherapy on electroconvulsive therapy outcomes: short-term efficacy and adverse effects.

CONTEXT Medication resistance is the leading indication for use of electroconvulsive therapy (ECT) in major depression. The practice of stopping antidepressant medications prior to ECT derived from studies in the 1960s and 1970s in nonresistant samples. There is also continuing controversy regarding the relative efficacy and adverse effects of right unilateral and bilateral ECT. OBJECTIVE To test the hypotheses that, compared with placebo, concomitant treatment with nortriptline or venlafaxine during the ECT course enhances short-term efficacy without a meaningful effect on adverse effects and reduces the rate of post-ECT relapse, and to test the hypotheses that high-dose, right-sided, unilateral ECT is equivalent in efficacy to moderate-dosage bilateral ECT and retains advantages with respect to cognitive adverse effects. DESIGN Prospective, randomized, triple-masked, placebo-controlled study conducted from 2001 through 2005. SETTING Three university-based hospitals. PATIENTS Of approximately 750 consecutive patients referred for ECT, 319 with a major depressive episode consented, were randomized to pharmacological or ECT treatment conditions, and received at least 1 ECT treatment. MAIN OUTCOME MEASURES Scores on the Hamilton Rating Scale for Depression, remission rate following completion of ECT, and selective measures of cognitive adverse effects. RESULTS Treatment with nortriptyline enhanced the efficacy and reduced the cognitive adverse effects of ECT relative to placebo. Venlafaxine resulted in a weaker degree of improvement and tended to worsen cognitive adverse effects. High-dosage right unilateral ECT did not differ or was superior to bilateral ECT in efficacy and resulted in less severe amnesia. CONCLUSIONS The efficacy of ECT is substantially increased by the addition of an antidepressant medication, but such medications may differ in whether they reduce or increase cognitive adverse effects. High-dose, right-sided, unilateral ECT is at least equivalent to moderate-dosage bilateral ECT in efficacy, but retains advantages with respect to cognitive adverse effects.

Altered networks in bothersome tinnitus: a functional connectivity study

BackgroundThe objective was to examine functional connectivity linked to the auditory system in patients with bothersome tinnitus. Activity was low frequency (< 0.1 Hz), spontaneous blood oxygenation level-dependent (BOLD) responses at rest. The question was whether the experience of chronic bothersome tinnitus induced changes in synaptic efficacy between co-activated components. Functional connectivity for seed regions in auditory, visual, attention, and control networks was computed across all 2 mm3 brain volumes in 17 patients with moderate-severe bothersome tinnitus (Tinnitus Handicap Index: average 53.5 ± 3.6 (range 38-76)) and 17 age-matched controls.ResultsIn bothersome tinnitus, negative correlations reciprocally characterized functional connectivity between auditory and occipital/visual cortex. Negative correlations indicate that when BOLD response magnitudes increased in auditory or visual cortex they decreased in the linked visual or auditory cortex, suggesting reciprocally phase reversed activity between functionally connected locations in tinnitus. Both groups showed similar connectivity with positive correlations within the auditory network. Connectivity for primary visual cortex in tinnitus included extensive negative correlations in the ventral attention temporoparietal junction and in the inferior frontal gyrus and rostral insula - executive control network components. Rostral insula and inferior frontal gyrus connectivity in tinnitus also showed greater negative correlations in occipital cortex.ConclusionsThese results imply that in bothersome tinnitus there is dissociation between activity in auditory cortex and visual, attention and control networks. The reciprocal negative correlations in connectivity between these networks might be maladaptive or reflect adaptations to reduce phantom noise salience and conflict with attention to non-auditory tasks.

Does Cerebellar LTD Mediate Motor Learning? Toward a Resolution without a Smoking Gun

It should be clear from the above discussion that the putative role of cerebellar LTD will continue to be a debated issue. There is neither a smoking gun experiment that establishes a causal link nor are all four of our criteria solidly satisfied. Even so, these criteria can serve as a road map leading to firmer ground, and we are struck by how far the journey has progressed. Consider, for example, the relative status of these criteria for cerebellar LTD relative to hippocampal LTP and spatial learning. For LTP, the only criterion that has been addressed seriously is necessity for learning, with results approximately equivalent to LTD and eyelid conditioning. Thus, despite the work remaining to be done, the evidence linking LTD to motor learning is better established than for many other form of plasticity in the vertebrate nervous system. With more work, we may eventually find that Marrs theory was more prophetic than emetic.*To whom correspondence should be addressed.

Covariation of Alternative Measures of Responding in Rabbit (Oryctolagus cuniculus) Eyeblink Conditioning During Acquisition Training and Tone Generalization

The likelihood, size, and speed of eyelid movements are thought to covary during the acquisition and expression of conditioning in rabbits (Oryctolagus cuniculus) and are generally accepted as interchangeable measures of the associative strength activated by the conditioned stimulus (CS). To test this assumption, the authors examined the patterns of covariation in these eyelid movement measures in acquisition and stimulus generalization in the upper eyelid and nictitating membrane. Rather than the expected covariation among these measures, eyelid movement magnitudes during the CS were distributed in approximately a bimodal manner. That is, eyelid activity consisted largely of a mixture of very small (< 0.125 mm) baseline measurements and larger (> 1 mm) movements. The results are discussed with respect to their implications for real-time models of eyelid conditioning.

Cognitive Improvement Following Treatment in Late-Life Depression: Relationship to Vascular Risk and Age of Onset

OBJECTIVES To test the hypothesis that the degree of vascular burden and/or age of onset may influence the degree to which cognition can improve during the course of treatment in late-life depression. DESIGN Measurement of cognition both before and following 12 weeks of treatment with sertraline. SETTING University medical centers (Washington University and Duke University). PARTICIPANTS One hundred sixty-six individuals with late-life depression. INTERVENTION Sertraline treatment. MEASUREMENTS The cognitive tasks were grouped into five domains (language, processing speed, working memory, episodic memory, and executive function). We measured vascular risk using the Framingham Stroke Risk Profile measure. We measured T2-based white matter hyperintensities using the Fazekas criteria. RESULTS Both episodic memory and executive function demonstrated significant improvement among adults with late-life depression during treatment with sertraline. Importantly, older age, higher vascular risk scores, and lower baseline Mini-Mental State Examination scores predicted less change in working memory. Furthermore, older age, later age of onset, and higher vascular risk scores predicted less change in executive function. CONCLUSIONS These results have important clinical implications in that they suggest that a regular assessment of vascular risk in older adults with depression is necessary as a component of treatment planning and in predicting prognosis, both for the course of the depression itself and for the cognitive impairments that often accompany depression in later life.

Repetitive transcranial magnetic stimulation treats postpartum depression.

BACKGROUND Postpartum depression (PPD) is a prevalent illness, affecting 10-15% of new mothers. PPD is the most common complication of childbirth and is a significant public health concern. It is known to adversely impact maternal-infant bonding, childrearing practices, and can lead to suicide and infanticide. The current treatment approaches to PPD are suboptimal. Many mothers are reluctant to take medication because of concerns about side effects or exposure of their newborn infant through breastfeeding. The specific aims of this study were to (1) examine acute treatment effectiveness, (2) examine response durability, and (3) assess an effect of repetitive transcranial magnetic stimulation (rTMS) on maternal bonding. METHODS Nine antidepressant-free women with PPD were given 20 rTMS treatments over 4 weeks (10Hz, 120% motor threshold, left dorsolateral prefrontal cortex). Multiple characteristics were assessed at baseline and throughout treatment. Duration of effect was assessed at 30 days, 3 months and 6 months posttreatment. RESULTS Friedmans tests were conducted on Hamilton Rating Scale for Depression-24 item (HRSD-24), Edinburgh Postnatal Depression Scale (EPDS), Inventory of Depressive Symptomatology-Self-Report (IDS-SR) and Clinical Global Impressions-Severity (CGI-S) scores to compare performances at four time points (baseline, end of Week 2, end of Week 4, and 180-day follow-up). Overall, these results revealed a significant reduction in depressive symptoms by the end of Week 2 of treatment. Analyses yielded a medium effect size (r=0.68) on the primary outcome variable (HRSD-24). Of note, all nine patients remained in treatment for the complete 4 weeks, did not miss any treatment sessions and eight participants achieved remission of symptoms, defined as a HRSD<10 and a CGI-S=1. Analysis of follow-up data indicated robustness of the rTMS treatment over time. At 6-month follow-up, of the eight women that remitted, seven remained in remission without further psychiatric intervention, including the addition of medication and one was lost to follow-up. Results also indicated a significant improvement in bonding. CONCLUSIONS Our results demonstrate promising results for the use of rTMS in the treatment of PPD. Further randomized, sham-controlled studies need to be completed.

Effects of severe bothersome tinnitus on cognitive function measured with standardized tests

Neurocognitive tests compared abilities in people with bothersome tinnitus against an age-, gender-, and education-matched normative population. Participants between 18 and 60 years had subjective, unilateral or bilateral, nonpulsatile tinnitus for >6 months and a Tinnitus Handicap Inventory score of ≥38. Results from a first testing session showed deficits in learning, learning rates, immediate recall of heard words, and use of a serial order encoding strategy. Initial reliance on serial order encoding and, later, increased intrusion of incorrect words towards normal levels might indicate a less demanding strategy to compensate for weakness in associative memory for semantic categories.

Treatment of Catatonia with Ultrabrief Right Unilateral Electroconvulsive Therapy: A Case Series

Catatonia is a syndrome heterogeneous with regard to presentation and etiology. Electroconvulsive therapy (ECT) remains the first-line treatment for catatonia. Literature review reveals only a few published case reports on the use of right unilateral (RUL) ECT in catatonia, 1 case report on ultrabrief RUL ECT, and an absence of evidence on the relative effectiveness and tolerability of RUL versus bilateral ECT in treating catatonia. In contrast, there are multiple reports in the literature of robustly dosed bilateral ECT, often administered on consecutive days. Reasons for choosing this intervention over the better-tolerated RUL treatment include assumptions about its relative speed and/or breadth of efficacy. Here we present a case series of 13 catatonic patients treated in an academic center over the course of the last 3 years. Our experience suggests that ultrabrief RUL ECT can rapidly and effectively treat catatonia from diverse etiologies.