Ziv Williams

Human anterior cingulate neurons and the integration of monetary reward with motor responses

Nat. Neurosci. 7, 1370–1375 (2004) A reference was deleted from this paper during the production process. It should have read as follows: 17. Botvinick, M., Nystrom, L.E., Fissell, K., Carter, C.S. & Cohen, J.D. Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature402, 179–181 (1999).

Human dorsal anterior cingulate cortex neurons mediate ongoing behavioural adaptation

The ability to optimize behavioural performance when confronted with continuously evolving environmental demands is a key element of human cognition. The dorsal anterior cingulate cortex (dACC), which lies on the medial surface of the frontal lobes, is important in regulating cognitive control. Hypotheses about its function include guiding reward-based decision making, monitoring for conflict between competing responses and predicting task difficulty. Precise mechanisms of dACC function remain unknown, however, because of the limited number of human neurophysiological studies. Here we use functional imaging and human single-neuron recordings to show that the firing of individual dACC neurons encodes current and recent cognitive load. We demonstrate that the modulation of current dACC activity by previous activity produces a behavioural adaptation that accelerates reactions to cues of similar difficulty to previous ones, and retards reactions to cues of different difficulty. Furthermore, this conflict adaptation, or Gratton effect, is abolished after surgically targeted ablation of the dACC. Our results demonstrate that the dACC provides a continuously updated prediction of expected cognitive demand to optimize future behavioural responses. In situations with stable cognitive demands, this signal promotes efficiency by hastening responses, but in situations with changing demands it engenders accuracy by delaying responses.

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.

Cell diversity and network dynamics in photosensitive human brain organoids

In vitro models of the developing brain such as three-dimensional brain organoids offer an unprecedented opportunity to study aspects of human brain development and disease. However, the cells generated within organoids and the extent to which they recapitulate the regional complexity, cellular diversity and circuit functionality of the brain remain undefined. Here we analyse gene expression in over 80,000 individual cells isolated from 31 human brain organoids. We find that organoids can generate a broad diversity of cells, which are related to endogenous classes, including cells from the cerebral cortex and the retina. Organoids could be developed over extended periods (more than 9 months), allowing for the establishment of relatively mature features, including the formation of dendritic spines and spontaneously active neuronal networks. Finally, neuronal activity within organoids could be controlled using light stimulation of photosensitive cells, which may offer a way to probe the functionality of human neuronal circuits using physiological sensory stimuli.

Visually Guided Movements Suppress Subthalamic Oscillations in Parkinson's Disease Patients

There is considerable evidence that abnormal oscillatory activity in the basal ganglia contributes to the pathogenesis of Parkinsons disease. However, little is known regarding the relationship of oscillations to volitional movements. Our goal was to evaluate the dynamics of oscillatory activity at rest and during movement. We performed microelectrode recordings from the subthalamic nucleus (STN) of patients undergoing deep brain stimulation surgery. During recordings, the patients used a joystick to guide a cursor to one of four targets on a monitor. We recorded 184 cells and 47 pairs of cells in 11 patients. At rest, 26 cells (14%) demonstrated significant oscillatory activity, with a mean frequency of 18 Hz. During movement, this oscillatory activity was either reduced or completely abolished in all of the cells. At rest, 18 pairs (38%) of cells in five patients exhibited synchronized oscillatory activity, with a mean frequency of 15 Hz. In 17 of the 18 pairs, both of the cells exhibited oscillations, and, in one pair, only one of the cells was oscillatory. These synchronized oscillations were also significantly decreased with movement. There was a strong inverse correlation between firing rates and oscillatory activity. As the firing rates increased with movement, there was a decrease in oscillatory activity. These findings suggest that visually guided movements are associated with a dampening and desynchronization of oscillatory activity in STN neurons. One possible explanation for these observations is that the increased cortical drive associated with movement preparation and execution leads to a transient dampening of STN oscillations, hence facilitating movement.

Value of PET in the Assessment of Patients with Neurofibromatosis Type 1

OBJECTIVE The objective of our study was to investigate the use of PET in the detection of malignant peripheral nerve sheath tumors (MPNSTs) in patients with neurofibromatosis type 1 (NF1). MATERIALS AND METHODS Forty-five patients with NF1 who underwent whole-body PET for suspected MPNST based on clinical symptoms or radiologic examinations were retrospectively evaluated. Ten patients underwent additional carbon-11 (11C) methionine PET because of equivocal 18F-FDG PET findings or because of a discrepancy between the FDG PET and clinical findings. PET images were evaluated for the distribution and uptake pattern, and the standardized uptake values (SUVs) were obtained. Twenty-seven patients underwent biopsy or surgery of the detected lesions and 18 patients were followed up clinically and with repeat imaging studies. RESULTS Fifty lesions were identified on FDG PET. There were eight false-positive results and one false-negative on FDG PET. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FDG PET in detecting MPNSTs in patients with NF1 were 95%, 72%, 71%, 95%, and 82%, respectively. Using 11C methionine PET in combination with FDG PET reduced the number of false-positive results from eight to two, which increased the specificity from 72% to 91%. In five patients, 11C methionine FDG PET contributed additional information about nontarget lesions that influenced treatment planning. CONCLUSION FDG PET is a sensitive technique in the detection of MPNSTs in patients with NF1. The addition of 11C methionine PET increases specificity in equivocal cases. PET may improve preoperative tumor staging by detecting metastases or second primary tumors, which often are present in patients with NF1.

Experience with Microelectrode Guided Subthalamic Nucleus Deep Brain Stimulation

OBJECTIVE: Subthalamic deep brain stimulation (DBS) has rapidly become the standard surgical therapy for medically refractory Parkinson disease. However, in spite of its wide acceptance, there is considerable variability in the technical approach. This study details our technique and experience in performing microelectrode recording (MER) guided subthalamic nucleus (STN) DBS in the treatment of Parkinson disease. METHODS: Forty patients underwent surgery for the implantation of 70 STN DBS electrodes. Stereotactic localization was performed using a combination of magnetic resonance and computed tomographic imaging. We used an array of three microelectrodes, separated by 2 mm, for physiological localization of the STN. The final location was selected based on MER and macrostimulation through the DBS electrode. RESULTS: The trajectory selected for the DBS electrode had an average pass through the STN of 5.6 ± 0.4 mm on the left and 5.7 ± 0.4 mm on the right. The predicted location was used in 42% of the cases but was modified by MER in the remaining 58%. Patients were typically discharged on the second postoperative day. Eighty-five percent of patients were sent home, 13% required short-term rehabilitation, and one patient required long-term nursing services. Seven complications occurred over 4 years. Four patients suffered small hemorrhages, one patient experienced a lead migration, one developed an infection of the pulse generator, and one patient suffered from a superficial cranial infection. CONCLUSION: Simultaneous bilateral MER-guided subthalamic DBS is a relatively safe and well-tolerated procedure. MER plays an important role in optimal localization of the DBS electrodes.

Efficacy results of a 52-week, randomised, double-blind, safety study of a calcipotriol/betamethasone dipropionate two-compound product (Daivobet/Dovobet/Taclonex) in the treatment of psoriasis vulgaris.

Background: The calcipotriol/betamethasone dipropionate two-compound product is safe and effective in the short-term treatment of psoriasis. Objective: The primary objective was to investigate the safety of two treatment regimens involving use of the two-compound product over 52 weeks. The efficacy results are presented here. Methods: Six hundred and thirty-four patients were randomised double-blind to treatment (once daily, when required) with either: 52 weeks of two-compound product (two-compound group), 52 weeks of alternating 4-week periods of two-compound product and calcipotriol (alternating group), or 4 weeks of two-compound product followed by 48 weeks of calcipotriol (calcipotriol group). Results: There was a trend towards a difference between treatments from the overall treatment effect for the percentage of satisfactory responses for each patient during the study (p = 0.071). This appeared to be due to the comparison of the two-compound and calcipotriol groups (p = 0.025). Conclusion: There was a trend towards the efficacy of the two-compound product used for up to 52 weeks being better than that of 4 weeks of the two-compound product followed by 48 weeks of calcipotriol.

Using Point Process Models to Compare Neural Spiking Activity in the Subthalamic Nucleus of Parkinson's Patients and a Healthy Primate

Placement of deep brain stimulating electrodes in the subthalamic nucleus (STN) to treat Parkinsons disease (PD) also allows the recording of single neuron spiking activity. Analyses of these unique data offer an important opportunity to better understand the pathophysiology of PD. Despite the point process nature of PD neural spiking activity, point process methods are rarely used to analyze these recordings. We develop a point process representation of PD neural spiking activity using a generalized linear model to describe long- and short-term temporal dependencies in the spiking activity of 28 STN neurons from seven PD patients and 35 neurons from one healthy primate (surrogate control) recorded, while the subjects executed a directed-hand movement task. We used the point process model to characterize each neurons bursting, oscillatory, and directional tuning properties during key periods in the task trial. Relative to the control neurons, the PD neurons showed increased bursting, increased 10-30 Hz oscillations, and increased fluctuations in directional tuning. These features, which traditional methods failed to capture accurately, were efficiently summarized in a single model in the point process analysis of each neuron. The point process framework suggests a useful approach for developing quantitative neural correlates that may be related directly to the movement and behavioral disorders characteristic of PD.

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.