Alice W. Flaherty

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial

BACKGROUND Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinsons disease. METHODS Patients aged 30-75 years who had progressive levodopa-responsive Parkinsons disease and an overnight off-medication unified Parkinsons disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. FINDINGS Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two). INTERPRETATION The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinsons disease and shows the promise for gene therapy for neurological disorders. FUNDING Neurologix.

Two input systems for body representations in the primate striatal matrix: experimental evidence in the squirrel monkey

The striatum is important in basal ganglia motor control and movement disorders. In this study we demonstrate the existence of two distinct sensorimotor cortical input systems to the striatum of the squirrel monkey. The first is a group of discrete zones in the extrastriosomal matrix of the putamen (“matrisomes”) that receive somatotopically organized projections from both the body map in ipsilateral primary motor cortex (MI) and maps in ipsilateral primary somatosensory cortex (SI). The second system is a group of matrisomes in largely different locations that receive somatotopically organized inputs from contralateral MI but not SI. Intracortical microstimulation and multiunit recording were used to guide deposits of multiple anterograde tracers in MI and SI. Striosome/matrix architecture was demonstrated by enkephalin immunohistochemistry. We found that inputs from regions of ipsilateral MI and SI that represented the same body parts sent projections to the same matrisomes of the ipsilateral putamen. Contralateral MI sent its strongest inputs to matrisomes that tended to interdigitate with those receiving inputs from ipsilateral SI and MI, except the contralateral MI face region, which sent projections that overlapped those from the ipsilateral MI face region. MI regions representing axial body parts (trunk and face) sent stronger representations to the contralateral putamen than did those representing distal parts (hand and foot). SI sent no contralateral projection. Thus, with the exception of the face representation, inputs from contralateral and ipsilateral body representations may alternate in the primate striatal matrix, an arrangement reminiscent of the alternating ocular dominance columns in visual cortex. Ipsilateral SI and MI and contralateral MI all innervated matrisomes intermingled with striosomes and with matrisomes not receiving sensorimotor cortical input. The patchiness of these maps is thus unlike the smoother somatotopic maps of sensorimotor cortex, and is also unlike the fractured somatotopy reported for the cerebellum.

Frontotemporal and dopaminergic control of idea generation and creative drive

This article presents a three‐factor anatomical model of human idea generation and creative drive, focusing on interactions between the temporal lobes, frontal lobes, and limbic system. Evidence is drawn from functional imaging, drug studies, and lesion analysis. Temporal lobe changes, as in hypergraphia, often increase idea generation, sometimes at the expense of quality. Frontal lobe deficits may decrease idea generation, in part because of rigid judgments about an ideas worth. These phenomena are clearest in verbal creativity, and roughly parallel the pressured communication of temporal lobe epilepsy, mania, and Wernickes aphasia—compared to the sparse speech and cognitive inflexibility of depression, Brocas aphasia, and other frontal lobe lesions. The phenomena also shape non‐linguistic creativity, as in that of frontotemporal dementia. The appropriate balance between frontal and temporal activity is mediated by mutually inhibitory corticocortical interactions. Mesolimbic dopamine influences novelty seeking and creative drive. Dopamine agonists and antagonists have opposite effects on goal‐directed behavior and hallucinations. Creative drive is not identical to skill—the latter depends more on neocortical association areas. However, drive correlates better with successful creative output than skill does. Traditional neuroscientific models of creativity, such as the left brain – right brain hemispheric model, emphasize skills primarily, and stress art and musical skill at the expense of language and mathematics. The three‐factor model proposed here predicts findings in a broad range of normal and pathological states and can be tested in many experimental paradigms. J. Comp. Neurol. 493:147–153, 2005.

Deep brain stimulation of the anterior internal capsule for the treatment of Tourette syndrome: technical case report.

OBJECTIVE AND IMPORTANCE: Medical treatment of Tourette syndrome is often ineffective or is accompanied by debilitating side effects, therefore prompting the need to evaluate surgical therapies. CLINICAL PRESENTATION: We present the case of a 37-year-old woman with severe Tourette syndrome since the age of 10 years. Her symptoms included frequent vocalizations and severe head and arm jerks that resulted in unilateral blindness. Trials of more than 40 medications and other therapies had failed to relieve the tics. INTERVENTION: We implanted bilateral electrodes in the anterior limb of the internal capsule, terminating in the vicinity of the nucleus accumbens. At 18-month follow-up, optimal stimulation continued to lower her tic frequency and severity significantly. CONCLUSION: Our findings suggest that stimulation of the anterior internal capsule may be a safe and effective procedure for the treatment of Tourette syndrome.

Laterality, somatotopy and reproducibility of the basal ganglia and motor cortex during motor tasks

We investigated the basal ganglia, motor cortex area 4, and supplementary motor area (SMA) using functional magnetic resonance imaging (fMRI) and five motor tasks: switching between finger and toe movements, writing, finger tapping, pronation/supination, and saccadic eye movements. We found reliable activation in the caudate nucleus and putamen in single subjects without the need for inter-subject averaging. Percent signal changes in basal ganglia were smaller by a factor of three than those in SMA or motor cortex (1% vs. 2.5-3%). There was a definite foot-dorsal, hand-ventral basal ganglia somatotopy, similar to prior data from primates. Saccadic eye movements activated the caudate nucleus significantly more than the other tasks did. Unilateral movements produced bilateral activation in the striatum even when motor cortex activation was unilateral. Surprisingly, bilateral performance of the tasks led, on average, to consistently smaller basal ganglia activation than did unilateral performance (P<0.001), suggesting less inhibition of contralateral movements during bilateral tasks. Moreover, there was a striking dominance pattern in basal ganglia motor activation: the left basal ganglia were more active than the right for right handers, regardless of the hand used. This lateralization appears much stronger than that previously reported for motor cortex. Comparisons of inter-subject and intra-subject reproducibility indicated a much larger variability in basal ganglia and SMA compared to motor cortex, in spite of similar percent signal changes in the latter two structures.

Basal ganglia activity remains elevated after movement in focal hand dystonia.

Although previous studies of focal hand dystonia have detected cortical sensorimotor abnormalities, little is known about the role of the basal ganglia in this disorder. We report here that when focal hand dystonic patients performed finger‐tapping tasks, functional magnetic resonance imaging showed persisting elevations of basal ganglia activity after the tasks ended. We posit that inhibitory control of the basal ganglia may be faulty in focal hand dystonia, and that the increases we observe in “resting” activity may mask basal ganglia abnormalities in standard imaging contrast analyses.

Microelectrode-Guided Deep Brain Stimulation for Tourette Syndrome: Within-Subject Comparison of Different Stimulation Sites

Background: As medical therapy for Tourette syndrome (TS) is ineffective in a small subset of patients, surgical interventions, including deep brain stimulation at various sites, have been developed in recent years. Case Description: We present the case of a 40-year-old woman with TS whose severe tics had caused unilateral blindness. Despite trials of more than 40 medications, her symptoms improved significantly only after placement of bilateral deep brain stimulators in the anterior inferior internal capsule. However, symptomatic improvement was not complete, and her electrode connections eventually became permanently damaged by the remaining retrocollic jerks. She underwent removal of the internal capsule electrodes and placement of centromedian nucleus thalamic stimulators with significantly improved tic control. Conclusion: Whereas the anterior internal capsule site had also produced psychiatric side effects such as altered mood and impulse control, the thalamic site has not done so to date. Thus, distinct surgical targets for TS may be appropriate for patients with specific comorbidities.

From symphony to cacophony : Pathophysiology of the human basal ganglia in Parkinson disease

Despite remarkable advances, the relationship between abnormal neuronal activity and the clinical manifestations of Parkinson disease (PD) remains unclear. Numerous hypotheses have emerged to explain the relationship between neuronal activity and symptoms such as tremor, rigidity and akinesia. Among these are the antagonist balance hypothesis wherein increased firing rates in the indirect pathway inhibits movement; the selectivity hypothesis wherein loss of neuronal selectivity leads to an inability to select or initiate movements; the firing pattern hypothesis wherein increased oscillation and synchronization contribute to tremor and disrupt information flow; and the learning hypothesis, wherein the basal ganglia are conceived as playing an important role in learning sensory-motor associations which is disrupted by the loss of dopamine. Deep brain stimulation (DBS) surgery provides a unique opportunity to assess these different ideas since neuronal activity can be directly recorded from PD patients. The emerging data suggest that the pathophysiologic changes include derangements in the overall firing rates, decreased neuronal selectivity, and increased neuronal oscillation and synchronization. Thus, elements of all hypotheses are present, emphasizing that the loss of dopamine results in a profound and multifaceted disruption of normal information flow through the basal ganglia that ultimately leads to the signs and symptoms of PD.

Unrecognized vitamin D3 deficiency is common in Parkinson disease Harvard Biomarker Study

Objective: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). Methods: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. Results: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson’s Disease Rating Scale scores at baseline and during follow-up. Conclusions: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D–deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

The role of the basal ganglia in bimanual coordination

The functional anatomical role of the basal ganglia in bimanual coordination is unknown. Utilizing functional MRI (fMRI) at 3 T, we analyzed brain activity during three different typing tasks. The first task consisted of typing with parallel finger movements (moving left to right with four fingers on both hands). The second task was mirror movements (moving little finger to index finger on both hands), and the third task compared a resting condition with right-handed unimanual typing (moving little finger to index finger). Task dependent BOLD activity in the supplementary motor area (SMA) and dorsolateral premotor areas was observed. In addition, activation patterns were present in the cerebellar vermis during bimanual coordination tasks, with greater activation in the parallel than in the mirror condition. Finally, we also identified activity in the putamen during the tasks described above. Interestingly, putaminal activity was greatest during the period of motor task initiation, and activity during this period was greatest in the parallel condition. Our results suggest a critical role of the basal ganglia in the neural control of bimanual coordination.