Plasticity in the adult human somatosensory thalamus

grantor: University of TorontoRepresentational plasticity has been well documented in experimental animals. However in humans, somatotopographic reorganization has only been anecdotally observed. Recent studies have suggested that cortical representation of body parts can change in humans; however the extent of reorganization is unknown and no attempts have been made to determine the contribution of subcortical structures to cortical plasticity. The aim of this thesis was to determine (i) whether plasticity exists in the human at the thalamic level and (ii) what the possible mechanisms involved are. 'I'. Long-term deafferentation was associated with different patterns of thalamic organization as determined by receptive (RF) and projected field (PF) mapping. In patients with leg/foot deafferentation there was an expansion of "trunk" representation and 4 of 5 limb amputees displayed an enlarged stump representation. Patients with face deafferentation had a significantly larger region of thalamus from which microstimulation evoked PFs on the face. 'II'. Two mechanisms have been proposed to account for such alterations in representation: sprouting of new connections and unmasking of previously present, relatively ineffective connections. The unmasking hypothesis was investigated by temporarily deafferenting cells with RFs located on the lidocaine-blocked digit. Most of these neurons displayed an improvement in, or an appearance of, new responses to mechanical stimulation of adjacent digits. 'III'. To identify the relatively ineffective connections responsible for this phenomenon, the RFs of single units and nearby sites were subjected to electrical stimulation (ES) and in some cases repetitive mechanical stimulation (RMS). Responses from within the RF were excitatory and of short latency (SLRs, 20 ms). Most cells (87%) responded to ES and RMS applied outside their RF and these responses were of long latency (LLRs, 42 ms), although some showed both SLRs and LLRs. 'IV'. Excessive cutaneous stimulation of one skin surface has also resulted in alterations in representation in the cortex of experimental animals. Patients with tremor, or increased afferent input to movement-related neurons, were found to have a larger region of movement-related representation. Despite limited thalamic exploration and the inherent problems with data collection in patients, when I-IV are examined together and interpreted in light of animal models, one can conclude that plasticity is indeed possible in the human somatosensory system and present at the thalamic level. The clinical importance of plasticity may be two-fold: both beneficial in that it may aid recovery from injury and detrimental in its possible maintenance of pain and tremor. (Abstract shortened by UMI.)Ph.D

Time and frequency-dependent modulation of local field potential synchronization by deep brain stimulation.

High-frequency electrical stimulation of specific brain structures, known as deep brain stimulation (DBS), is an effective treatment for movement disorders, but mechanisms of action remain unclear. We examined the time-dependent effects of DBS applied to the entopeduncular nucleus (EP), the rat homolog of the internal globus pallidus, a target used for treatment of both dystonia and Parkinson's disease (PD). We performed simultaneous multi-site local field potential (LFP) recordings in urethane-anesthetized rats to assess the effects of high-frequency (HF, 130 Hz; clinically effective), low-frequency (LF, 15 Hz; ineffective) and sham DBS delivered to EP. LFP activity was recorded from dorsal striatum (STR), ventroanterior thalamus (VA), primary motor cortex (M1), and the stimulation site in EP. Spontaneous and acute stimulation-induced LFP oscillation power and functional connectivity were assessed at baseline, and after 30, 60, and 90 minutes of stimulation. HF EP DBS produced widespread alterations in spontaneous and stimulus-induced LFP oscillations, with some effects similar across regions and others occurring in a region- and frequency band-specific manner. Many of these changes evolved over time. HF EP DBS produced an initial transient reduction in power in the low beta band in M1 and STR; however, phase synchronization between these regions in the low beta band was markedly suppressed at all time points. DBS also enhanced low gamma synchronization throughout the circuit. With sustained stimulation, there were significant reductions in low beta synchronization between M1-VA and STR-VA, and increases in power within regions in the faster frequency bands. HF DBS also suppressed the ability of acute EP stimulation to induce beta oscillations in all regions along the circuit. This dynamic pattern of synchronizing and desynchronizing effects of EP DBS suggests a complex modulation of activity along cortico-BG-thalamic circuits underlying the therapeutic effects of GPi DBS for conditions such as PD and dystonia

Dosing of Electrical Parameters in Deep Brain Stimulation (DBS) for Intractable Depression: A Review of Clinical Studies

Background: The electrical parameters used for deep brain stimulation (DBS) in movement disorders have been relatively well studied, however for the newer indications of DBS for psychiatric indications these are less clear. Based on the movement disorder literature, use of the correct stimulation parameters should be crucial for clinical outcomes. This review examines the stimulation parameters used in DBS studies for treatment resistant depression (TRD) and their relevance to clinical outcome and brain targets.Methods: We examined the published studies on DBS for TRD archived in major databases. Data on stimulus parameters (frequency, pulse width, amplitude), stimulation mode, brain target, efficacy, safety, and duration of follow up were extracted from 29 observational studies including case reports of patients with treatment resistant unipolar, bipolar, and co-morbid depression.Results: The algorithms commonly used to optimize efficacy were increasing amplitude followed by changing the electric contacts or increasing pulse width. High frequency stimulation (>100 Hz) was applied in most cases across brain targets. Keeping the high frequency stimulation constant, three different combinations of parameters were mainly used: (i) short pulse width (60–90 us) and low amplitude (0–4 V), (ii) short pulse width and high amplitude (5–10 V), (iii) long pulse width (120–450 us) and low amplitude. There were individual variations in clinical response to electrical dosing and also in the time of clinical recovery. There was no significant difference in mean stimulation parameters between responders and non-responders suggesting a role for stimulation unrelated factors in response.Conclusions: Although limited by open trials and small sample size, three optimal stimulation parameter combinations emerged from this review. Studies are needed to assess the comparative efficacy and safety of these combinations, such as a registry of data from patients undergoing DBS for TRD with individual data on stimulation parameters

Dosing of Electrical Parameters in Deep Brain Stimulation (DBS) for Intractable Depression: A Review of Clinical Studies

Background: The electrical parameters used for deep brain stimulation (DBS) in movement disorders have been relatively well studied, however for the newer indications of DBS for psychiatric indications these are less clear. Based on the movement disorder literature, use of the correct stimulation parameters should be crucial for clinical outcomes. This review examines the stimulation parameters used in DBS studies for treatment resistant depression (TRD) and their relevance to clinical outcome and brain targets. Methods: We examined the published studies on DBS for TRD archived in major databases. Data on stimulus parameters (frequency, pulse width, amplitude), stimulation mode, brain target, efficacy, safety, and duration of follow up were extracted from 29 observational studies including case reports of patients with treatment resistant unipolar, bipolar, and co-morbid depression. Results: The algorithms commonly used to optimize efficacy were increasing amplitude followed by changing the electric contacts or increasing pulse width. High frequency stimulation (>100 Hz) was applied in most cases across brain targets. Keeping the high frequency stimulation constant, three different combinations of parameters were mainly used: (i) short pulse width (60-90 us) and low amplitude (0-4 V), (ii) short pulse width and high amplitude (5-10 V), (iii) long pulse width (120-450 us) and low amplitude. There were individual variations in clinical response to electrical dosing and also in the time of clinical recovery. There was no significant difference in mean stimulation parameters between responders and non-responders suggesting a role for stimulation unrelated factors in response. Conclusions: Although limited by open trials and small sample size, three optimal stimulation parameter combinations emerged from this review. Studies are needed to assess the comparative efficacy and safety of these combinations, such as a registry of data from patients undergoing DBS for TRD with individual data on stimulation parameters

Attention and grasping in Parkinson's disease: Effects of treatment and disease stages

Objective: To compare the attentional resources devoted to reach-to-grasp movements at different stages of Parkinson’s disease (PD), on and off treatment, relative to intact controls. Background: Reach-to-grasp movements are a critical component of activities of daily living. The grasping movements of patients with PD are characterized by a reliance on cues and visual feedback, not seen in the very automatic movements of intact controls (Azulay et al, 2006). PD patients appear to devote significant attentional resources to their movements; dual-task performance is a well-known area of difficulty for PD patients. To date, the role of attention in everyday reach-to-grasp movements has not been examined, though the implications for performance of activities of daily living are clearly considerable. Methods: The performance of three patient groups [de novo (n=11); moderate (n=24); and surgical (STN DBS; n=14)] was compared with age matched controls (n=24) on a dual task paradigm involving grasping and a concurrent cognitive task designed to consume attention. Attentional resources were measured with standardized tests. Participants reached to grasp functional objects with handles (e.g. a comb). Handles were turned away from participants; an appropriate grasp was scored if they successfully picked up the object by the handle. Between and within group comparisons were made using ANOVA and t-tests. Results: The control group and the de novo group not yet on medication displayed strong evidence of automaticity in their movements; when performing a challenging spatial imagery task, they made the same number of appropriate grasps as when they picked up the objects without a concurrent task. In contrast, for the moderate and the surgical groups, performing the concurrent task resulted in fewer appropriate grasps, and there was no improvement while on treatment (medication and stimulation, respectively). Only the surgical group showed decreased divided attention on standardized measures (>-0.7 SD below their normative group). Conclusions: Grasping appears to shift from an automatic to an attention demanding process by the moderate stages of PD. This may be a coping mechanism designed to safely adapt to reduced motor function, or it may reflect pathology in the mechanisms underlying grasping movements. References: Azulay JP, Mesure S, and Blin O. 2006. J Neurol Sci, 248(1-2): 192-195

Summary of major effects.

<p>Arrows signify significant increases or decreases (p<0.05) in oscillation power or functional connectivity (assessed using debiased weighted phase lag index; WPLI). Bold arrows represent early effects and thin arrows represent late effects, which are more widespread.</p

High-frequency (HF) EP DBS suppresses acute EP-induced beta oscillations in all recorded regions.

<p><b>A.</b> Representative raw (black) and filtered (6–30 Hz; red) voltage traces from M1 (calibration: 200 ms, 0.2 mV) and time-frequency spectrograms showing effects of acute EP stimulation before (left) and after (right) 90 minutes of high-frequency (HF) EP DBS. <b>B.</b> Changes in induced oscillation power according to region and time point. Low-frequency (LF) EP DBS does not suppressed induced oscillations as HF DBS does. Error bars represent S.E.M. * = significantly different from SHAM and LF (p<0.05).</p

Electrode placements and experimental design.

<p><b>A:</b> Left: Dots show recording electrode placements in striatum (STR), primary motor cortex (M1), and ventroanterior thalamus (VA) and DBS electrode placements in entopeduncular nucleus (EP), and; numbers represent antero-posterior distance from bregma. Overlapping placements have been omitted for clarity, and placements have been collapsed into the same plane and may be slightly anterior or posterior (±∼200 µm) to the indicated distance from bregma. Right: Enlarged sections showing placements in EP and photomicrograph showing marked electrode location in EP. Scale bar = 1 mm. <b>B:</b> Outline of stimulation and recording protocol.</p