Intermittent subthalamic nucleus deep brain stimulation induces risk-aversive behavior in human subjects.

The subthalamic nucleus (STN) is a small almond-shaped subcortical structure classically known for its role in motor inhibition through the indirect pathway within the basal ganglia. Little is known about the role of the STN in mediating cognitive functions in humans. Here, we explore the role of the STN in human subjects making decisions under conditions of uncertainty using single-neuron recordings and intermittent deep brain stimulation (DBS) during a financial decision-making task. Intraoperative single-neuronal data from the STN reveals that on high-uncertainty trials, spiking activity encodes the upcoming decision within a brief (500 ms) temporal window during the choice period, prior to the manifestation of the choice. Application of intermittent DBS selectively prior to the choice period alters decisions and biases subject behavior towards conservative wagers.

It is Electric! Electroconvulsive Therapy for Refractory Central Pain and Comorbid Psychiatric Disease.

Central pain syndromes are a complex, diverse group of clinical conditions that are poorly understood. We present a patient with progressive, debilitating central pain and co-existing mood disorders that was refractory to multimodal pharmacologic and nonpharmacologic therapies, but that ultimately responded to electroconvulsive therapy (ECT). The patient described it at various times as her skin being "lit on fire," "stabbed," "squeezed like a boa constrictor," or itching unbearably. She underwent a course of three sequential ECT treatments during her hospitalization and it dramatically decreased her pain. She began maintenance ECT, and a rate of roughly one treatment a month provided persistent pain suppression. Despite this lack of evidence, ECT has a favorable safety profile and can be considered in the therapeutic armamentarium for patients who have exhausted standard treatment regimens who continue to have suffering in the setting of central pain syndromes and coexisting mood disorders.

Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson's disease.

BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

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.

Studying task-related activity of individual neurons in the human brain.

Single-neuronal studies remain the gold standard for studying brain function. Here we describe a protocol for studying task-related single-neuronal activity in human subjects during neurosurgical procedures involving microelectrode recordings. This protocol has two phases: a preoperative phase and an intraoperative phase. During the preoperative phase, we discuss informed consent, equipment setup and behavioral testing. During the intraoperative phase, we discuss the procedure for microelectrode recordings. Because patients are often awake during these procedures, this protocol can be performed in conjunction with behavioral tasks for studying a variety of cognitive functions. We describe the protocol in detail and provide two examples of expected results. In addition, we discuss the potential difficulties and pitfalls related to intraoperative studies. This protocol takes ∼1.5 h to complete.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study.

BACKGROUND: Mutations in the α-synuclein gene (SNCA) cause autosomal dominant forms of Parkinson's disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome-wide association studies. METHODS: We genotyped a prioritized noncoding variant in SNCA intron 4 in 344 patients with Parkinson's disease and 275 controls from the longitudinal Harvard NeuroDiscovery Center Biomarker Study. RESULTS: The common minor allele of rs2736990 was associated with elevated disease susceptibility (odds ratio, 1.40; P = .0032). CONCLUSIONS: This result increases confidence in the notion that in many clinically well-characterized patients, genetic variation in SNCA contributes to "sporadic" disease.

Temporary interruption of deep brain stimulation for Parkinson's disease during outpatient electroconvulsive therapy for major depression: a novel treatment strategy.

The safety of electroconvulsive therapy (ECT) in patients with deep brain stimulation (DBS) has not been established. Cases reported had no adverse events, but DBS was withheld throughout the weeks of the ECT course. The authors report the first case of temporary interruption of DBS only during the minutes of each outpatient ECT.

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 Parkinson's disease. METHODS: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's 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 Parkinson's disease and shows the promise for gene therapy for neurological disorders. FUNDING: Neurologix.

Brain illness and creativity: mechanisms and treatment risks.

Brain diseases and their treatment may help or hurt creativity in ways that shape quality of life. Increased creative drive is associated with bipolar disorder, depression, psychosis, temporal lobe epilepsy, frontotemporal dementia, Parkinson disease treatments, and autism. Creativity depends on goal-driven approach motivation from midbrain dopaminergic systems. Fear-driven avoidance motivation is of less aid to creativity. When serotonin and norepinephrine lower motivation and flexible behaviour, they can inhibit creativity. Hemispheric lateralization and frontotemporal connections must interact to create new ideas and conceptual schemes. The right brain and temporal lobe contribute skill in novelty detection, while the left brain and frontal lobe foster approach motivation and more easily generate new patterns of action from the novel perceptions. Genes and phenotypes that increase plasticity and creativity in tolerant environments with relaxed selection pressure may confer risk in rigorous environments. Few papers substantively address this important but fraught topic. Antidepressants (ADs) that inhibit fear-driven motivation, such as selective serotonin reuptake inhibitors, sometimes inhibit goal-oriented motivation as well. ADs that boost goal-directed motivation, such as bupropion, may remediate this effect. Benzodiazepines and alcohol may be counterproductive. Although dopaminergic agonists sometimes stimulate creativity, their doing so may inappropriately disinhibit behaviour. Dopamine antagonists may suppress creative motivation; lithium and anticonvulsant mood stabilizers may do so less. Physical exercise and REM sleep may help creativity. Art therapy and psychotherapy are not well studied. Preserving creative motivation can help creativity and other aspects of well-being in all patients, not just artists or researchers.

Ventral intermediate thalamic stimulation for monoclonal gammopathy-associated tremor: case report.

BACKGROUND AND IMPORTANCE: Peripheral and central sensory loss are often associated with significant tremor or sensory ataxia, which can be highly refractory to medical therapy. CLINICAL PRESENTATION: We present the case of a 67-year-old man with progressive and debilitating intention tremor from monoclonal gammopathy-associated peripheral neuropathy. The patient was implanted with bilateral thalamic deep brain stimulator electrodes under microelectrode guidance. Following optimization of stimulation parameters, the patient's appendicular tremor and gait improved, as did his general activities of daily living. CONCLUSION: These initial findings suggest that deep brain stimulation may benefit not only tremor presumed to originate from central nervous system dysfunction, but also tremor originating peripherally from neuropathy-related sensory loss.

Prospective assessment of stereotactic ablative surgery for intractable major depression.

BACKGROUND: Despite therapeutic advances for major depression, a subset of patients with this disorder does not respond to conventional treatment. Stereotactic ablative procedures such as anterior cingulotomy have been performed in severely affected, treatment-resistant patients, but the long-term results of such procedures are not fully understood. METHODS: Findings are reported for 33 patients with severe treatment-resistant major depression who underwent ablative stereotactic procedures (dorsal anterior cingulotomy followed if necessary by subcaudate tractotomy). Preoperative and long-term postoperative Beck Depression Inventory scores were obtained along with postoperative Clinical Global Improvement values. Both were analyzed to evaluate patients' responses to the surgical procedure(s). RESULTS: At mean follow-up of 30 months after one or more stereotactic ablative procedures, 11 patients (33.3%) were classified as responders, 14 (42.4%) were partial responders, and 8 (24.2%) did not respond to the surgical procedure(s). Among those (17) who underwent only one procedure, seven (41.2%) responded, whereas six (35.3%) and four (23.5%) showed partial or no response, respectively. Among patients who required multiple surgical procedures, four patients (25%) responded, whereas eight (50%) and four (25%) patients demonstrated partial or no responses, respectively, at long-term follow-up evaluations. CONCLUSIONS: Approximately 75% of depression patients previously resistant to antidepressant therapies received partial or substantial benefit from stereotactic ablative procedures. Those requiring only a single anterior cingulotomy tended to demonstrate more pronounced responses than patients who underwent multiple surgical procedures.

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.

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.

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 idea's worth. These phenomena are clearest in verbal creativity, and roughly parallel the pressured communication of temporal lobe epilepsy, mania, and Wernicke's aphasia-compared to the sparse speech and cognitive inflexibility of depression, Broca's 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.