Claire E. Wilcox

Purkinje Cell Expression of a Mutant Allele of SCA1 in Transgenic Mice Leads to Disparate Effects on Motor Behaviors, Followed by a Progressive Cerebellar Dysfunction and Histological Alterations

Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant neurological disorder caused by the expansion of a CAG repeat encoding a polyglutamine tract. Work presented here describes the behavioral and neuropathological course seen in mutant SCA1 transgenic mice. Behavioral tests indicate that at 5 weeks of age mutant mice have an impaired performance on the rotating rod in the absence of deficits in balance and coordination. In contrast, these mutantSCA1 mice have an increased initial exploratory behavior. Thus, expression of the mutant SCA1 allele within cerebellar Purkinje cells has divergent effects on the motor behavior of juvenile animals: a compromise of rotating rod performance and a simultaneous enhancement of initial exploratory activity. With age, these animals develop incoordination with concomitant progressive Purkinje neuron dendritic and somatic atrophy but relatively little cell loss. Therefore, the eventual development of ataxia caused by the expression of a mutant SCA1 allele is not the result of cell death per se, but the result of cellular dysfunction and morphological alterations that occur before neuronal demise.

Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study

Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants’ responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5–8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. TRIAL REGISTRATION: NCT02061293

Enhanced Cue Reactivity and Fronto-striatal Functional Connectivity in Cocaine Use Disorders

Chronic cocaine use is associated with enhanced cue reactivity to drug stimuli. However, it may also alter functional connectivity (fcMRI) in regions involved in processing drug stimuli. Our aims were to evaluate the neural regions involved in subjective craving and how fcMRI may be altered in chronic cocaine users. Fourteen patients with a confirmed diagnosis of cocaine abuse or dependence (CCA) and 16 gender, age, and education-matched healthy controls (HC) completed a cue reactivity task and a resting state scan while undergoing functional magnetic resonance imaging. CCA showed increased activation compared to HC in left dorsolateral prefrontal and bilateral occipital cortex in response to cocaine cues but not to appetitive control stimuli. Moreover, CCA also showed increased activation within the orbital frontal cortex (OFC) for cocaine cues relative to the appetitive stimuli during a hierarchical regression analysis. A negative association between subjective craving and activity in medial posterior cingulate gyrus (PCC) was also observed for CCA. CCA exhibited increased resting state correlation (positive) between cue-processing seed regions (OFC and ventral striatum), and negative connectivity between cue-processing regions and PCC/precuneus. These alterations in fcMRI may partially explain the neural basis of increased drug cue salience in CCA.

Relationship of striatal dopamine synthesis capacity to age and cognition

Past research has demonstrated that performance on frontal lobe-dependent tasks is associated with dopamine system integrity and that various dopamine system deficits occur with aging. The positron emission tomography (PET) radiotracer 6-[18F]fluoro-l-m-tyrosine (FMT) is a substrate of the dopamine-synthesizing enzyme, aromatic amino acid decarboxylase (AADC). Studies using 6-[18F]fluorodopa (FDOPA) (another AADC substrate) to measure how striatal PET signal and age relate have had inconsistent outcomes. The varying results occur in part from tracer processing that renders FDOPA signal subject to aspects of postrelease metabolism, which may themselves change with aging. In contrast, FMT remains a purer measure of AADC function. We used partial volume-corrected FMT PET scans to measure age-related striatal dopamine synthesis capacity in 21 older (mean, 66.9) and 16 younger (mean, 22.8) healthy adults. We also investigated how striatal FMT signal related to a cognitive measure of frontal lobe function. Older adults showed significantly greater striatal FMT signal than younger adults. Within the older group, FMT signal in dorsal caudate (DCA) and dorsal putamen was greater with age, suggesting compensation for deficits elsewhere in the dopamine system. In younger adults, FMT signal in DCA was lower with age, likely related to ongoing developmental processes. Younger adults who performed worse on tests of frontal lobe function showed greater FMT signal in right DCA, independent of age effects. Our data suggest that higher striatal FMT signal represents nonoptimal dopamine processing. They further support a relationship between striatal dopamine processing and frontal lobe cognitive function.

Cognitive control in alcohol use disorder: deficits and clinical relevance.

Abstract Cognitive control refers to the internal representation, maintenance, and updating of context information in the service of exerting control over thoughts and behavior. Deficits in cognitive control likely contribute to difficulty in maintaining abstinence in individuals with alcohol use disorders (AUD). In this article, we define three cognitive control processes in detail (response inhibition, distractor interference control, and working memory), review the tasks measuring performance in these areas, and summarize the brain networks involved in carrying out these processes. Next, we review evidence of deficits in these processes in AUD, including both metrics of task performance and functional neuroimaging. Finally, we explore the clinical relevance of these deficits by identifying predictors of clinical outcome and markers that appear to change (improve) with treatment. We observe that individuals with AUD experience deficits in some, but not all, metrics of cognitive control. Deficits in cognitive control may predict clinical outcome in AUD, but more work is necessary to replicate findings. It is likely that performance on tasks requiring cognitive control improves with abstinence, and with some psychosocial and medication treatments. Future work should clarify which aspects of cognitive control are most important to target during treatment of AUD.

Correlations of striatal dopamine synthesis with default network deactivations during working memory in younger adults

Age‐related deficits have been demonstrated in working memory performance and in the dopamine system thought to support it. We performed positron emission tomography (PET) scans on 12 younger (mean 22.7 years) and 19 older (mean 65.8 years) adults using the radiotracer 6‐[18F]‐fluoro‐L‐m‐tyrosine (FMT), which measures dopamine synthesis capacity. Subjects also underwent functional magnetic resonance imaging (fMRI) while performing a delayed recognition working memory task. We evaluated age‐related fMRI activity differences and examined how they related to FMT signal variations in dorsal caudate within each age group. In posterior cingulate cortex and precuneus (PCC/Pc), older adults showed diminished fMRI deactivations during memory recognition compared with younger adults. Greater task‐induced deactivation (in younger adults only) was associated both with higher FMT signal and with worse memory performance. Our results suggest that dopamine synthesis helps modulate default network activity in younger adults and that alterations to the dopamine system may contribute to age‐related changes in working memory function. Hum Brain Mapp, 2011.

Neural Circuitry of Impaired Emotion Regulation in Substance Use Disorders

Impaired emotion regulation contributes to the development and severity of substance use disorders (substance disorders). This review summarizes the literature on alterations in emotion regulation neural circuitry in substance disorders, particularly in relation to disorders of negative affect (without substance disorder), and it presents promising areas of future research. Emotion regulation paradigms during functional magnetic resonance imaging are conceptualized into four dimensions: affect intensity and reactivity, affective modulation, cognitive modulation, and behavioral control. The neural circuitry associated with impaired emotion regulation is compared in individuals with and without substance disorders, with a focus on amygdala, insula, and prefrontal cortex activation and their functional and structural connectivity. Hypoactivation of the rostral anterior cingulate cortex/ventromedial prefrontal cortex (rACC/vmPFC) is the most consistent finding across studies, dimensions, and clinical populations (individuals with and without substance disorders). The same pattern is evident for regions in the cognitive control network (anterior cingulate and dorsal and ventrolateral prefrontal cortices) during cognitive modulation and behavioral control. These congruent findings are possibly related to attenuated functional and/or structural connectivity between the amygdala and insula and between the rACC/vmPFC and cognitive control network. Although increased amygdala and insula activation is associated with impaired emotion regulation in individuals without substance disorders, it is not consistently observed in substance disorders. Emotion regulation disturbances in substance disorders may therefore stem from impairments in prefrontal functioning, rather than excessive reactivity to emotional stimuli. Treatments for emotion regulation in individuals without substance disorders that normalize prefrontal functioning may offer greater efficacy for substance disorders than treatments that dampen reactivity.

Overeating Behavior and Striatal Dopamine with 6-[18F]-Fluoro-L--Tyrosine PET

Eating behavior may be affected by dopamine synthesis capacity. In this study, 6-[18F]-fluoro-L-m-tyrosine (FMT) positron emission tomography (PET) uptake in striatal subregions was correlated with BMI (kg/m2) and an estimate of the frequency of prior weight loss attempts in 15 healthy subjects. BMI was negatively correlated with FMT uptake in the dorsal caudate. Although the association between BMI and FMT uptake in the dorsal caudate was not significant upon correction for age and sex, the association fell within the range of a statistical trend. Weight loss attempts divided by years trying was also negatively correlated with FMT uptake in the dorsal putamen (P = .05). These results suggest an association between low dorsal striatal presynaptic dopamine synthesis capacity and overeating behavior.

Hyperactivation of the cognitive control network in cocaine use disorders during a multisensory Stroop task

BACKGROUND It has been suggested that individuals with cocaine use disorders (chronic cocaine abusers, CCA) have impairments in cognitive control, which likely contribute to impairments in decision making around drug use and relapse. However, deficits in cognitive control have currently only been studied under conditions of unisensory stimulation, which may not be reflective of more realistic multisensory drug cues. METHODS The current study employed functional magnetic resonance imaging (fMRI) to measure neuronal activity during a multisensory numeric Stroop task. RESULTS Despite few differences in reaction time, recently abstinent CCA (N=14) exhibited increased activation in prefrontal cortex, striatum and thalamus during cognitive control relative to a group of carefully matched controls (N=16). Importantly, these neuronal differences were relatively robust in classifying patients from controls (approximately 90% accuracy) and evident during conditions of both low (slow stimulus presentation rate) and relatively high (faster stimulus presentation rate) cognitive demand. In addition, CCA also failed to deactivate the default-mode network during high frequency visual trials. CONCLUSIONS In summary, current results indicate compensatory activation within the cognitive control network in recently abstinent CCA to achieve similar levels of behavioral performance.

The Subjective Experience of Pain: An FMRI Study of Percept-Related Models and Functional Connectivity

OBJECTIVE Previous work suggests that the perception of pain is subjective and dependent on individual differences in physiological, emotional, and cognitive states. Functional magnetic resonance imaging (FMRI) studies have used both stimulus-related (nociceptive properties) and percept-related (subjective experience of pain) models to identify the brain networks associated with pain. Our objective was to identify the network involved in processing subjective pain during cold stimuli. METHODS The current FMRI study directly contrasted a stimulus-related model with a percept-related model during blocks of cold pain stimuli in healthy adults. Specifically, neuronal activation was modelled as a function of changes in stimulus intensity vs as a function of increasing/decreasing levels of subjective pain corresponding to changes in pain ratings. In addition, functional connectivity analyses were conducted to examine intrinsic correlations between three proposed subnetworks (sensory/discriminative, affective/motivational, and cognitive/evaluative) involved in pain processing. RESULTS The percept-related model captured more extensive activation than the stimulus-related model and demonstrated an association between higher subjective pain and activation in expected cortical (dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, insula, dorsal anterior cingulate cortex [dACC] extending into pre-supplementary motor area) and subcortical (thalamus, striatum) areas. Moreover, connectivity results supported the posited roles of dACC and insula as key relay sites during neural processing of subjective pain. In particular, anterior insula appeared to link sensory/discriminative regions with regions in the other subnetworks, and dACC appeared to serve as a hub for affective/motivational, cognitive/evaluative, and motor subnetworks. CONCLUSIONS Using a percept-related model, brain regions involved in the processing of subjective pain during the application of cold stimuli were identified. Connectivity analyses identified linkages between key subnetworks involved in processing subjective pain.