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1.  The late positive potential, emotion and apathy in Parkinson’s disease 
Neuropsychologia  2013;51(5):960-966.
Parkinson’s disease is associated with emotional changes including depression, apathy, and anxiety. The current study investigated emotional processing in non-demented individuals with Parkinson disease (PD) using an electrophysiological measure, the centro-parietal late positive potential (LPP). Non-demented patients with Parkinson’s disease (n=17) and healthy control participants (n=16) viewed pleasant, neutral, and unpleasant pictures while EEG was recorded from a 64-channel geodesic net. The Parkinson patients did not differ from controls in terms of early electrophysiological components that index perceptual processing (occipital P100, N150, P250). Parkinson patients, however, showed reduced LPP amplitude specifically when viewing unpleasant, compared to pleasant, pictures as well as when compared to controls, consistent with previous studies suggesting a specific difference in aversive processing between PD patients and healthy controls. Importantly, LPP amplitude during unpleasant picture viewing was most attenuated for patients reporting high apathy. The data suggest that apathy in PD may be related to a deficit in defensive activation, and may be indexed cortically using event-related potentials.
PMCID: PMC3681426  PMID: 23320979
Parkinson’s disease; ERP; Late positive potential; Apathy; Emotion
2.  Emotion and ocular responses in Parkinson’s Disease 
Neuropsychologia  2011;49(12):3247-3253.
Parkinson’s disease (PD) is a neurodegenerative disease that affects motor, cognitive, and emotional functioning. Previous studies reported reduced skin conductance responses in PD patients, compared to healthy older adults when viewing emotionally arousing pictures. Attenuated skin conductance changes in PD may reflect peripheral autonomic dysfunction (e.g., reduced nerve endings at the sweat gland) or, alternatively, a more central emotional deficit. The aim of the current study was to investigate a second measure of sympathetic arousal—change in pupil dilation. Eye movements, a motor-based correlate of emotional processing, were also assessed. Results indicated that pupil dilation was significantly greater when viewing emotional, compared to neutral pictures for both PD patients and controls. On the other hand, PD patients made fewer fixations with shorter scan paths, particularly when viewing pleasant pictures. These results suggest that PD patients show normal sympathetic arousal to affective stimuli (indexed by pupil diameter), but differences in motor correlates of emotion (eye movements.)
PMCID: PMC3384545  PMID: 21839756
emotion; arousal; Parkinson’s disease; pupil; eye movement
4.  Patient-Specific Analysis of the Relationship Between the Volume of Tissue Activated During DBS and Verbal Fluency 
NeuroImage  2010;54S1:S238-S246.
Deep brain stimulation (DBS) for the treatment of advanced Parkinson’s disease involves implantation of a lead with four small contacts usually within the subthalamic nucleus (STN) or globus pallidus internus (GPi). While generally safe from a cognitive standpoint, STN DBS has been commonly associated with a decrease in the speeded production of words, a skill referred to as verbal fluency. Virtually all studies comparing pre-surgical to post-surgical verbal fluency performance have detected a decrease with DBS. The decline may be attributable in part to the surgical procedures, yet the relative contributions of stimulation effects are not known. In the present study, we used patient-specific DBS computer models to investigate the effects of stimulation on verbal fluency performance. Specifically, we investigated relationships of the volume and locus of activated STN tissue to verbal fluency outcome. Stimulation of different electrode contacts within the STN did not affect total verbal fluency scores. However, models of activation revealed subtle relationships between the locus and volume of activated tissue and verbal fluency performance. At ventral contacts, more tissue activation inside the STN was associated with decreased letter fluency performance. At optimal contacts, more tissue activation within the STN was associated with improved letter fluency performance. These findings suggest subtle effects of stimulation on verbal fluency performance, consistent with the functional non-motor subregions/somatopy of the STN.
PMCID: PMC2908727  PMID: 20362061
verbal fluency; DBS; cognition; mood; microlesion
5.  Entorhinal cortex volume in older adults: Reliability and validity considerations for three published measurement protocols 
Measuring the entorhinal cortex (ERC) is challenging due to lateral border discrimination from the perirhinal cortex. From a sample of 39 nondemented older adults who completed volumetric image scans and verbal memory indices, we examined reliability and validity concerns for three ERC protocols with different lateral boundary guidelines (i.e., Goncharova, Dickerson, Stoub, & deToledo-Morrell, 2001; Honeycutt et al., 1998; Insausti et al., 1998). We used three novice raters to assess inter-rater reliability on a subset of scans (216 total ERCs), with the entire dataset measured by one rater with strong intra-rater reliability on each technique (234 total ERCs). We found moderate to strong inter-rater reliability for two techniques with consistent ERC lateral boundary endpoints (Goncharova, Honeycutt), with negligible to moderate reliability for the technique requiring consideration of collateral sulcal depth (Insausti). Left ERC and story memory associations were moderate and positive for two techniques designed to exclude the perirhinal cortex (Insausti, Goncharova), with the Insausti technique continuing to explain 10% of memory score variance after additionally controlling for depression symptom severity. Right ERC-story memory associations were nonexistent after excluding an outlier. Researchers are encouraged to consider challenges of rater training for ERC techniques and how lateral boundary endpoints may impact structure-function associations. (JINS, 2010, 1–10.)
PMCID: PMC3070302  PMID: 20937164
Insausti; Goncharova; Memory; Paragraph memory; Story memory; Alzheimer
6.  The trajectory of apathy after deep brain stimulation: From pre-surgery to 6 months post-surgery in Parkinson’s disease☆ 
Parkinsonism & related disorders  2011;17(3):182-188.
Deep brain stimulation (DBS) has been associated with increased apathy in patients with PD, yet studies lack longitudinal data and have not assessed differences between sites of implantation (i.e. STN versus GPi). We assessed apathy prior to surgery and 6 months post-surgery using a longitudinal designe–latent growth curve modeling. We hypothesized that apathy would increase post-surgery, and be related to subthalamic nucleus (versus globus pallidus interna) implantation. Forty-eight PD patients underwent unilateral surgery to either GPi or STN and completed the Apathy Scale prior to surgery and 2, 4, and 6 months post-surgery. Forty-eight matched PD controls completed the Apathy Scale at a 6-month interval. Results indicated apathy increased linearly from pre- to 6-months post-DBS by .66 points bi-monthly, while apathy in the control group did not change. There was no relationship between apathy and DBS site. Higher baseline depression was associated with higher baseline apathy, but not with change in apathy. Middle-aged adults (<65) had a steeper trajectory of apathy than older adults (≥65). Apathy trajectory was not related to motor severity, laterality of DBS, levodopa medication reduction, or motor changes after surgery.
PMCID: PMC3045850  PMID: 21256069
Parkinson’s disease; Apathy; Deep brain stimulation; Latent growth curve modeling
7.  Is the N-Back Task a Valid Neuropsychological Measure for Assessing Working Memory? 
The n-back is a putative working memory task frequently used in neuroimaging research; however, literature addressing n-back use in clinical neuropsychological evaluation is sparse. We examined convergent validity of the n-back with an established measure of working memory, digit span backward. The relationship between n-back performance and scores on measures of processing speed was also examined, as was the ability of the n-back to detect potential between-groups differences in control and Parkinson's disease (PD) groups. Results revealed no correlation between n-back performance and digit span backward. N-back accuracy significantly correlated with a measure of processing speed (Trail Making Test Part A) at the 2-back load. Relative to controls, PD patients performed less accurately on the n-back and showed a trend toward slower reaction times, but did not differ on any of the neuropsychological measures. Results suggest the n-back is not a pure measure of working memory, but may be able to detect subtle differences in cognitive functioning between PD patients and controls.
PMCID: PMC2770861  PMID: 19767297
Working memory; Executive function; Information processing speed; Parkinson's disease; Neuropsychology
8.  Dissociating apathy and depression in Parkinson disease 
Neurology  2006;67(1):33-38.
To examine the hypothesis that apathy is a core feature of Parkinson disease (PD) and that apathy can be dissociated from depression.
Eighty patients with PD and 20 patients with dystonia completed depression and apathy measures including the Marin Apathy Evaluation Scale (AES), Beck Depression Inventory (BDI), and Centers for Epidemiologic Studies–Depression Scale (CES-D).
There was a significantly higher severity and frequency of apathy in PD (frequency = 51%, 41/80) than in dystonia (frequency = 20%, 4/20). Apathy in the absence of depression was frequent in PD and did not occur in dystonia (PD = 28.8%, dystonia = 0%).
Patients with Parkinson disease (PD) experienced significantly higher frequency and severity of apathy when compared with patients with dystonia. Apathy may be a “core” feature of PD and occurs in the absence of depression.
PMCID: PMC2911155  PMID: 16832074
9.  Startle reflex hyporeactivity in Parkinson's disease: an emotion-specific or arousal-modulated deficit? 
Neuropsychologia  2009;47(8-9):1917-1927.
We previously reported that patients with Parkinson's disease (PD) demonstrate reduced psychophysiologic reactivity to unpleasant pictures as indexed by diminished startle eyeblink magnitude (Bowers et al., 2006). In the present study, we tested the hypothesis that this hyporeactivity was primarily driven by diminished reactivity to fear-eliciting stimuli as opposed to other types of aversive pictures. This hypothesis was based on previous evidence suggesting amygdalar abnormalities in PD patients coupled with the known role of the amygdala in fear processing. To test this hypothesis, 24 patients with Parkinson's disease and 24 controls viewed standardized sets of emotional pictures that depicted fear, disgust (mutilations, contaminations), pleasant, and neutral contents. Startle eyeblinks were elicited while subjects viewed these emotional pictures. Results did not support the hypothesis of a specific deficit to fear pictures. Instead, the PD patients had reduced reactivity to mutilation pictures relative to other types of negative pictures in the context of normal subjective ratings. Further analyses revealed that controls displayed a pattern of increased startle eyeblink magnitude for “high arousal” versus “low arousal” negative pictures, regardless of picture category, whereas startle eyeblink magnitude in the PD group did not vary by arousal level. These results suggest that previous findings of decreased aversion-modulated startle is driven by reduced reactivity to highly arousing negative stimuli rather than to a specific category (i.e., fear or disgust) of emotion stimuli.
PMCID: PMC2709833  PMID: 19428424
basal ganglia; emotion; neurophysiology; neurological disorders; neurodegenerative disorders
10.  Panic and fear induced by deep brain stimulation 
Mood, cognitive, and behavioural changes have been reported with deep brain stimulation (DBS) in the thalamus, globus pallidus interna, and anterior limb of the internal capsule/nucleus accumbens region.
To investigate panic and fear resulting from DBS.
Intraoperative DBS in the region of the right and then left anterior limb of the internal capsule and nucleus accumbens region was undertaken to treat a 52 year old man with treatment refractory obsessive‐compulsive disorder (OCD). Mood, anxiety, OCD, alertness, heart rate, and subjective feelings were recorded during intraoperative test stimulation and at follow up programming sessions.
DBS at the distal (0) contact (cathode 0−, anode 2+, pulse width 210 ms, rate 135 Hz, at 6 volts) elicited a panic attack (only seen at the (0) contact). The patient felt flushed, hot, fearful, and described himself as having a “panic attack.” His heart rate increased from 53 to 111. The effect (present with either device) was witnessed immediately after turning the device on, and abruptly ceased in the off condition
DBS of the anterior limb of the internal capsule and nucleus accumbens region caused severe “panic.” This response may result from activation of limbic and autonomic networks.
PMCID: PMC2077710  PMID: 16484657
deep brain stimulation; fear; panic
12.  Induction of mortality and malformation in Xenopus laevis embryos by water sources associated with field frog deformities. 
Environmental Health Perspectives  1998;106(12):841-848.
Water samples from several ponds in Minnesota were evaluated for their capacity to induce malformations in embryos of Xenopus laevis. The FETAX assay was used to assess the occurrence of malformations following a 96-hr period of exposure to water samples. These studies were conducted following reports of high incidences of malformation in natural populations of frogs in Minnesota wetlands. The purpose of these studies was to determine if a biologically active agent(s) was present in the waters and could be detected using the FETAX assay. Water samples from ponds with high incidences of frog malformations (affected sites), along with water samples from ponds with unaffected frog populations (reference sites), were studied. Initial experiments clearly showed that water from affected sites induced mortality and malformation in Xenopus embryos, while water from reference sites had little or no effect. Induction of malformation was dose dependent and highly reproducible, both with stored samples and with samples taken at different times throughout the summer. The biological activity of the samples was reduced or eliminated when samples were passed through activated carbon. Limited evidence from these samples indicates that the causal factor(s) is not an infectious organism nor are ion concentrations or metals responsible for the effects observed. Results do indicate that the water matrix has a significant effect on the severity of toxicity. Based on the FETAX results and the occurrence of frog malformations observed in the field, these studies suggest that water in the affected sites contains one or more unknown agents that induce developmental abnormalities in Xenopus. These same factors may contribute to the increased incidence of malformation in native species.
PMCID: PMC1533234  PMID: 9831545
14.  Effects of cocaine on simple reaction times and sensory thresholds in baboons. 
The effects of chronic, daily administration of cocaine on auditory and visual reaction times and thresholds were studied in baboons. Single intramuscular injections of cocaine hydrochloride (0.1 to 5.6 mg/kg) were given once daily for periods of 10 to 25 days, and were followed immediately by psychophysical tests designed to assess cocaine's effects on simple reaction times as on auditory and visual threshold functions. Consistent reductions in reaction times were frequently observed over the cocaine dose range of 0.32 to 1.0 mg/kg; at higher doses, either decreases or increases in reaction times were observed, depending upon the animal. Lowered reaction times generally occurred immediately following the 1st day's cocaine injection, and continued through all subsequent days during the dose administration period, suggesting little development of tolerance or sensitivity to these reaction-time effects. Reaction-time decreases showed a U-shaped dose-effect function. The greatest decreases in reaction times occurred from 0.32 to 1.0 mg/kg, and produced an average reaction-time decrease of 10 to 12%. Concurrently measured auditory and visual thresholds showed no systematic changes as a function of cocaine dose. Pausing was observed during performance of the psychophysical tasks, with the length of total session pause times being directly related to cocaine dose.
PMCID: PMC1334411  PMID: 8169572
15.  Cholinergic treatment of an amnestic man with a basal forebrain lesion: theoretical implications. 
Cholinergic deficient states, such as in Alzheimer's disease, are associated with amnesia. Therapeutic trials with cholinergic augmentation in Alzheimer's disease have had only equivocal results, but mechanisms other than cholinergic deficiency may contribute to the memory deficit. Normally the diagonal band of Broca provides much of the hippocampal cholinergic input. To learn if amnesia secondary to cholinergic deficiency can be ameliorated by cholinergic augmentation, we treated an amnestic man who had a lesion located primarily in the right diagonal band of Broca with physostigmine and lecithin. During the initial best-dose-finding phase, he demonstrated an inverted U-shaped curve for immediate recall of word lists, with peak performances at 3.0 and 3.5 mg of physostigmine. Single photon emission tomography showed decreased blood flow in the medial temporal region ipsilateral to the lesion at baseline, with a reversal of the asymmetry on 3.5 mg of physostigmine. A follow-up double-blind, placebo-controlled study on 3.5 mg of physostigmine, however, failed to demonstrate that cholinergic treatment improved memory.
PMCID: PMC1015375  PMID: 8270928
16.  Comprehension of prosody in Huntington's disease. 
Patients with Huntington's Disease (HD) who were without dementia were compared to unilateral stroke patients and controls as previously reported in 1983, to discover if they had a prosodic defect. Subjects were presented tape-recorded speech filtered sentences and asked to indicate the tone of voice as happy, sad or angry (affective prosody), or as a question, command or statement (propositional prosody). HD patients were impaired in comprehension of both types of prosody compared to controls but were not different from stroke patients. A second study compared early HD patients with at-risk siblings and spouse controls on comprehension of affective and propositional prosody, discrimination of both types of prosody, rhythm discrimination and tonal memory (Seashore tests). HD patients were impaired in both comprehension and discrimination of all types of prosody. HD patients were less accurate than at-risk patients on the tonal memory task but not on the rhythm discrimination task. These findings suggest compromise in ability to understand the more subtle prosodic aspects of communication which may contribute to social impairment of HD patients very early in the course of the disease.
PMCID: PMC488139  PMID: 2144017
17.  Aneurysms of the abdominal aorta: a 20-year study. 
One hundred and eighty-eight patients in whom the diagnosis of aneurysm of the abdominal aorta (AAA) was established after 1 January 1960 were followed until their deaths or to 31 December 1979. By the actuarial method, the cumulative 5-year risk of an intact aneurysm progressing to rupture was 35%; the observed 5-year survival rate for patients who had medical management for intact AAA was 30%, for patients who had elective surgery for AAA 74%, for patients who had emergency surgery for ruptured AAA 35%, and for those who did not have surgery for ruptured AAA 0%. Comparison of the non-operated and electively-operated groups of patients showed that the former was disproportionately weighted with older higher-risk patients, suggesting that the difference in survival rates for the two groups might be a reflection of patient selection rather than of surgical intervention. Comparison of the cumulative 5-year risk of rupture of an intact AAA with the cumulative 5-year mortality rate associated with elective surgery for intact AAA showed that elective surgery for intact AAA might be expected to result in a reduction in the cumulative 5-year mortality rates of patients with intact AAA.
PMCID: PMC1289945  PMID: 4045883
18.  Deaths and anaesthesia. 
PMCID: PMC1499713  PMID: 6811056
19.  Staffing of accident and emergency departments. 
British Medical Journal  1978;2(6152):1648.
PMCID: PMC1608892  PMID: 728775
22.  Abortion or contraception? 
British Medical Journal  1971;3(5772):476-477.
PMCID: PMC1800448  PMID: 5567781

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