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Background Deep brain stimulation of the subthalamic nucleus is a widely used adjunctive therapy for motor symptoms of Parkinson's disease, but with variable motor response. Predicting motor response remains difficult, and novel approaches may improve surgical outcomes as well as the understanding of pathophysiological mechanisms. The objective of this study was to determine whether preoperative resting-state functional connectivity MRI predicts motor response from deep brain stimulation of the subthalamic nucleus. Methods We collected preoperative resting-state functional MRI from 70 participants undergoing subthalamic nucleus deep brain stimulation. For this cohort, we analyzed the strength of STN functional connectivity with seeds determined by stimulation-induced (ON/OFF) 15 O H2 O PET regional cerebral blood flow differences in a partially overlapping group (n = 42). We correlated STN-seed functional connectivity strength with postoperative motor outcomes and applied linear regression to predict motor outcomes. Results Preoperative functional connectivity between the left subthalamic nucleus and the ipsilateral internal globus pallidus correlated with postsurgical motor outcomes (r = -0.39, P = 0.0007), with stronger preoperative functional connectivity relating to greater improvement. Left pallidal-subthalamic nucleus connectivity also predicted motor response to DBS after controlling for covariates. Discussion Preoperative pallidal-subthalamic nucleus resting-state functional connectivity predicts motor benefit from deep brain stimulation, although this should be validated prospectively before clinical application. These observations suggest that integrity of pallidal-subthalamic nucleus circuits may be critical to motor benefits from deep brain stimulation. © 2020 International Parkinson and Movement Disorder Society.

OBJECTIVE: To determine whether striatal dopamine (DA) release is affected by food ingestion and whether the DA response to high-calorie food images is greater in the fasted than fed state in people with obesity. METHODS: Striatal DA release was evaluated in 10 people with obesity and prediabetes after participants consumed a meal to satiation and after they fasted overnight, and in response to viewing images of high-calorie compared with low-calorie foods after consuming a meal to satiation or fasting overnight, by using positron emission tomography with [(11)C]raclopride injection. RESULTS: Striatal DA D2/D3 receptor availability was not different during fasted and fed conditions. Viewing images of high-calorie foods induced striatal DA release relative to viewing images of low-calorie foods (p

Background Chronic exposure to manganese (Mn) is a health concern in occupations such as welding because of well-established motor effects due to basal ganglia dysfunction. We hypothesized that cognitive control (the ability to monitor, manipulate, and regulate ongoing cognitive demands) would also be affected by chronic Mn exposure. Methods We examined the relationship between Mn exposure and cognitive control performance in 95 workers with varying intensity and duration (median 15.5 years) of exposure to welding fume. We performed linear regression to assess the association between exposure to Mn-containing welding fume and cognitive control tasks. Results Overall performance was inversely related to intensity of welding exposure (P = 0.009) and was driven by the Two-Back and Letter Number Sequencing tests that assess working memory (both P = 0.02). Conclusions Occupational exposure to Mn-containing welding fume may be associated with poorer working memory performance, and workers may benefit from practices that reduce exposure intensity. Am. J. Ind. Med. 60:181–188, 2017. © 2016 Wiley Periodicals, Inc.

In humans, the A1 (T) allele of the dopamine (DA) D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) TaqIA (rs1800497) single nucleotide polymorphism has been associated with reduced striatal DA D2/D3 receptor (D2/D3R) availability. However, radioligands used to estimate D2/D3R are displaceable by endogenous DA and are nonselective for D2R, leaving the relationship between TaqIA genotype and D2R specific binding uncertain. Using the positron emission tomography (PET) radioligand, (N-[(11) C]methyl)benperidol ([(11) C]NMB), which is highly selective for D2R over D3R and is not displaceable by endogenous DA, the current study examined whether DRD2/ANKK1 TaqIA genotype predicts D2R specific binding in two independent samples. Sample 1 (n = 39) was composed of obese and nonobese adults; sample 2 (n = 18) was composed of healthy controls, unmedicated individuals with schizophrenia, and siblings of individuals with schizophrenia. Across both samples, A1 allele carriers (A1+) had 5 to 12% less striatal D2R specific binding relative to individuals homozygous for the A2 allele (A1-), regardless of body mass index or diagnostic group. This reduction is comparable to previous PET studies of D2/D3R availability (10-14%). The pooled effect size for the difference in total striatal D2R binding between A1+ and A1- was large (0.84). In summary, in line with studies using displaceable D2/D3R radioligands, our results indicate that DRD2/ANKK1 TaqIA allele status predicts striatal D2R specific binding as measured by D2R-selective [(11) C]NMB. These findings support the hypothesis that DRD2/ANKK1 TaqIA allele status may modify D2R, perhaps conferring risk for certain disease states.

Aims To determine if children and young people aged < 23 years with Type 1 diabetes differ in academic ability from age-matched control subjects without Type 1 diabetes and whether academic scores are related to glycaemic control. Methods Using a cross-sectional study design, we administered cognitive and academic tests (Woodcock-Johnson III Spatial Relations, General Information, Letter-Word Recognition, Calculation and Spelling tests) to young people with Type 1 diabetes (n=61) and control subjects (n=26) aged 9–22 years. The groups did not differ in age or gender. Participants with Type 1 diabetes had a disease duration of 5–17.7 years. History of glycaemic control (HbA1c, diabetic ketoacidosis and severe hypoglycaemic episodes) was obtained via medical records and interviews. Results The participants with Type 1 diabetes had a lower mean estimated verbal intelligence (IQ) level compared with those in the control group (P=0.04). Greater exposure to hyperglycaemia over time was associated with lower spelling abilities within the group with Type 1 diabetes (P=0.048), even after controlling for age, gender, socio-economic status, blood glucose level at time of testing and verbal IQ (P=0.01). History of severe hypoglycaemia or ketoacidosis was not associated with differences in academic abilities. Conclusions In children and young people, Type 1 diabetes was associated with a lower verbal IQ. Moreover, increased exposure to hyperglycaemia was associated with lower spelling performance. These results imply that hyperglycaemia can affect cognitive function and/or learning processes that may affect academic achievement.

Objective We developed a novel method to map behavioral effects of deep brain stimulation (DBS) across a 3D brain region and to assign statistical significance after stringent Type I error correction. This method was applied to behavioral changes in Parkinson disease (PD) induced by subthalamic nucleus (STN) DBS to determine whether these responses depended on anatomical location of DBS.

Objectives In older adults with anxiety disorders, chronically elevated cortisol may contribute to cognitive impairment and elevated anxiety. We conducted a pilot study with mifepristone, a glucocorticoid receptor antagonist, as a potential treatment for late-life anxiety disorders and co-occurring cognitive dysfunction. Methods Fifteen individuals 60 years and older with an anxiety disorder plus cognitive dysfunction participated in the 12-week study. In the first week, participants were randomly assigned to mifepristone 300 mg daily or placebo. In the subsequent 3 weeks, all participants received mifepristone 300 mg. Mifepristone was then discontinued, and the participants were reassessed 8 weeks later. We examined the following: (1) cognitive changes; (2) worry symptom severity; (3) safety and tolerability; and (4) salivary cortisol before, during, and after mifepristone exposure. Results Overall safety, tolerability, and high retention supported the feasibility of this research. Participants with higher baseline cortisol levels (peak cortisol >6.0 ng/ml, n = 5) showed improvements in memory, executive function, and worry severity after 3-4 weeks of mifepristone with persistent memory and worry improvements 8 weeks after mifepristone discontinuation. Individuals with low-to-normal baseline cortisol (n = 8) showed little to no improvement. As expected, cortisol levels rose during mifepristone exposure and returned to pretreatment levels 8 weeks after mifepristone discontinuation. In the first week of treatment, there were no differences between placebo-treated and mifepristone-treated participants. Conclusion The results of this pilot study warrant further testing of antiglucocorticoid agents in late-life anxiety disorders with co-occurring cognitive dysfunction. Mifepristone is hypothesized to have benefits in patients with evidence of glucocorticoid excess. Directions for further study are discussed.

Background Mindfulness-based stress reduction (MBSR) has the potential to reduce worry and improve cognitive functioning. Objectives In this treatment development project, we examined MBSR in older adults with worry symptoms and co-occurring cognitive dysfunction. We examined (i) acceptability of MBSR, (ii) whether MBSR needs to be lengthened providing more repetition, (iii) MBSR's benefits for worry reduction and cognitive improvements, and (iv) continued use of MBSR techniques during follow-up. Methods Two sites (St. Louis and San Diego) enrolled individuals aged 65 years or older with significant anxiety-related distress plus subjective cognitive dysfunction, into traditional 8-session MBSR groups and 12-session groups that had the same content but more repetition of topics and techniques. We examined measures of mindfulness, worry, and a neuropsychological battery focused on memory and executive function before and after the MBSR program, and we followed up participants for 6 months after the completion of MBSR regarding their continued use of its techniques. Results Participants (N = 34) showed improvements in worry severity, increases in mindfulness, and improvements in memory as measured by paragraph learning and recall after a delay, all with a large effect size. Most participants continued to use MBSR techniques for 6 months post-instruction and found them helpful in stressful situations. There was no evidence that the extended 12-week MBSR produced superior cognitive or clinical outcomes, greater satisfaction, or greater continuation of MBSR techniques than 8-week MBSR. Conclusions These preliminary findings are promising for the further testing and use of MBSR in older adults suffering from clinical worry symptoms and co-occurring cognitive dysfunction. These are common problems in a broad range of older adults, many of whom have anxiety and mood disorders; therefore, stress reduction intervention for them may have great public health value. Copyright © 2014 John Wiley & Sons, Ltd.

Previous PET imaging studies have demonstrated mixed findings regarding dopamine D2/D3 receptor availability in obese relative to nonobese humans. Nonspecific D2/D3 radioligands do not allow for separate estimation of D2 receptor (D2R) and D3 receptor (D3R) subtypes of the D2 receptor family, which may play different roles in behavior and are distributed differently throughout the brain. These radioligands are also displaceable by endogenous dopamine, confounding interpretation of differences in receptor availability with differing levels of dopamine release. The present study used PET imaging with the D2R-selective radioligand (N-[(11)C] methyl)benperidol ([(11)C]NMB), which is nondisplaceable by endogenous dopamine, to estimate D2R specific binding (BPND) and its relationship to body mass index (BMI) and age in 15 normal-weight (mean BMI = 22.6 kg/m(2)) and 15 obese (mean BMI = 40.3 kg/m(2)) men and women. Subjects with illnesses or taking medications that interfere with dopamine signaling were excluded. Striatal D2R BPND was calculated using the Logan graphical method with cerebellum as a reference region. D2R BPND estimates were higher in putamen and caudate relative to nucleus accumbens, but did not differ between normal-weight and obese groups. BMI values did not correlate with D2R BPND . Age was negatively correlated with putamen D2R BPND in both groups. These results suggest that altered D2R specific binding is not involved in the pathogenesis of obesity per se and underscore the need for additional studies evaluating the relationship between D3R, dopamine reuptake, or endogenous dopamine release and human obesity.

Huntington disease (HD) is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this article, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through "Large Deformation Diffeomorphic Metric Mapping" of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. On the basis of the relation to cortico-basal ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

Alterations of striatal and extrastriatal concentrations of the dopaminergic D2 receptor family, including subtypes D2 (D2R) and D3 (D3R), may play a role in the pathophysiology or treatment of movement and psychiatric disorders including Parkinson disease (Kaasinen et al., 2000a; Kaasinen et al., 2003; Smith and Villalba, 2008), dystonia (Karimi et al., 2011; Perlmutter et al., 1997), Huntington's disease (Pavese et al., 2003), restless legs syndrome (Cervenka et al., 2006; Connor et al., 2009), schizophrenia (Kegeles et al., 2010), social phobia (Schneier et al., 2000) and Tourette syndrome (Gilbert et al., 2006; Steeves et al., 2010). PET imaging with dopamine receptor radioligands provides an in vivo method to investigate such alterations. The most commonly used PET radioligands for the measurement of the D2 family of receptors include [11C] raclopride, [18F]fallypride and [11C]FLB 457. However, the disadvantages of using these radioligands is that they have near equal affinity for both D2R and D3R subtypes (Elsinga et al., 2006; Halldin et al., 1995; Mukherjee et al., 1999) and competition from endogenous dopamine may alter their uptake and retention in brain (Chou et al., 2000; Cropley et al., 2008; Dewey et al., 1992; Dewey et al., 1993; Montgomery et al., 2007; Riccardi et al., 2006; Seeman et al., 1989). These characteristics can be exploited in some experimental designs to measure endogenous dopamine release, but confound interpretation of specific binding levels since the PET measurement may reflect both the binding potential of D2R and D3R subtypes and levels of endogenous dopamine. Although pharmacologic distinction between D2R and D3R subtypes of the dopamine D2 receptor family has been accomplished only recently, the DNA and mRNA that code for these proteins are quite distinct (Chien et al., 2010; Gingrich and Caron, 1993; Sokoloff et al., 1990). Post-mortem radioligand receptor autoradiography of D2R and D3R in the human brain reveal different receptor binding site patterns throughout the brain (Beaulieu and Gainetdinov, 2011; Hall et al., 1996a, b; Murray et al., 1994). Receptor distribution and mRNA expression levels in humans and rodents as determined by receptor autoradiography and in situ hybridization indicate that D2R is distributed heterogeneously throughout the brain; high levels of D2R occur in the dorsal striatum and pole of the nucleus accumbens as well as extrastriatal and cortical regions whereas D3R is highly distributed in limbic areas including the shell of the nucleus accumbens (Hall et al., 1996a, b; Missale et al., 1998; Sokoloff et al., 1992b; Vallone et al., 2000, Xu et al., 2010). However, recent autoradiography data from aged human brains demonstrate that D3R are distributed extensively throughout the striatum (Xu et al., 2011). Therefore, interpretation of previous D2/D3R distribution ratio reports should be viewed with caution; conflicting findings such as these indicate the need for in vivo study of D2R and D3R with PET radioligands specific for D2R or D3R in humans. The differences in regional binding patterns of the D2R subtypes indicate that D2R and D3R likely play different roles in reward, cognition, movement and psychiatric disorders. For example, abnormalities in striatal D3R may play a key role in the pathophysiology of dystonia (Karimi et al., 2011). Notably, antipsychotic drugs have a higher affinity for D2R over D3R (Civelli et al., 1993; Sokoloff et al., 1992), suggesting a larger role for the D2R subtype in neuropsychiatric disorders, or, alternatively, that the D3 subtype may represent a relatively unexplored therapeutic target for D3-selective antagonist antipsychotics. Currently, the relatively modestly D3-preferring PET radiotracer and dopamine agonist [11C]-PHNO has been used to measure D3 specific receptor types (Gallezot et al., 2011; Girgis et al., 2011; Tziortzi et al., 2011). Improved distinction between D2R and D3R binding in striatal and extrastriatal regions via PET imaging would provide a valuable clinical research tool for in vivo study of neuropsychiatric disorders. [18F]N-methylbenperidol ([18F]NMB) is a PET radioligand developed to measure D2R. It is an analog of the dopamine receptor antagonist benperidol of the butyrophenone structural class, has been clinically used as an antipsychotic drug (Reynolds, 1993), and has high affinity and selectivity for D2R (Karimi et al., 2011; Moerlein et al., 1995;, Suehiro et al., 1990). These latter characteristics have made butyrophenones compounds of interest in the search for PET dopamine receptor radioligands (Arnett et al., 1986; Moerlein et al, 1986, 1992, 1995; Suehiro et al., 1990). Selectivity of [18F]NMB and its analogues for D2 receptors over D1, serotonergic and adrenergic receptors has been demonstrated in vivo in baboon and in vitro in mice by unaltered striatal uptake after pretreatment with unlabeled receptor-specific antagonists and by displacement with unlabeled D2 antagonists (Arnett et al., 1985; Moerlein et al., 1995, 1997; Suehiro et al., 1990) [18F]NMB has more than 200-fold higher affinity for D2R than D3R, as recently demonstrated by in vitro radioligand binding assays in transfected cells that express D2 and D3 receptors (Karimi et al., 2011). [18F]NMB reversibly binds to D2R's (Moerlein et al., 1995, 1997; Suehiro et al., 1990) and resists competition from endogenous dopamine release, as demonstrated by lack of displacement by high dose intravenous amphetamine (Moerlein et al., 1997). Thus, [18F]NMB is an excellent candidate radioligand for unambiguous PET quantification of the D2R subtype in brain. Previous research demonstrated [18F]NMB's ability to specifically bind to D2R in striatum (Antenor-Dorsey et al., 2008; Karimi et al., 2011). However, PET measures of extrastriatal D2R specific binding with [18F]NMB has not yet been quantified. Given the importance of extrastriatal D2R binding in neuropsychiatric and movement disorders, it is necessary to determine whether PET using [18F]NMB can reliably measure D2R specific binding in these regions. We now report such PET imaging studies in healthy adults.