P. G. Ray

Differential cognitive and behavioral effects of carbamazepine and lamotrigine

Background: The relative cognitive and behavioral effects of lamotrigine compared with the older standard antiepileptic drugs (AED) are uncertain. Objective: To directly compare the cognitive and behavioral effects of carbamazepine and lamotrigine. Methods: The cognitive and behavioral effects of carbamazepine and lamotrigine were assessed in 25 healthy adults using a double-blind, randomized crossover design with two 10-week treatment periods. During each treatment condition, subjects received either lamotrigine (150 mg/day) or carbamazepine (mean 696 mg/day) adjusted to a dose to achieve midrange standard therapeutic blood levels (mean 7.6 μg/mL). Subjects were tested at the end of each AED treatment period and in three drug-free conditions (two pretreatment baselines and a final posttreatment period [1 month after last AED]). The neuropsychological test battery included 19 measures yielding 40 total variables. Results: Direct comparison of the two AED revealed significantly better performance on 19 (48%) variables for lamotrigine but none for carbamazepine. Differences spanned both objective cognitive and subjective behavioral measures, including cognitive speed, memory, graphomotor coding, neurotoxic symptoms, mood factors, sedation, perception of cognitive performance, and other quality-of-life perceptions. Comparison of carbamazepine with the nondrug average revealed significantly better performance for nondrug average on 24 (62%) variables but none for carbamazepine. Comparison of lamotrigine with nondrug average revealed better performance on one (2.5%) variable for nondrug average and on one (2.5%) variable for lamotrigine. Conclusion: Lamotrigine produces significantly fewer untoward cognitive and behavioral effects than carbamazepine at the dosages used in this study.

Gamma coherence and conscious perception.

BackgroundHigh-frequency (e.g., gamma 30 to 50 Hz) coherent neural activity has been postulated to underlie binding of independent neural assemblies and thus integrate processing across distributed neuronal networks to achieve a unified conscious experience. Prior studies suggest that gamma activity may play a role in perceptual mechanisms, but design limitations raise concerns. Thus, controversy exists as to the hypothesis that gamma activity is necessary for perceptual awareness. In addition, controversy exists as to whether the primary sensory cortices are involved directly in the mechanisms of conscious perception or just in processes prior to conscious awareness. Objective To investigate the relation of gamma coherence and perception. MethodsDigital intracranial electrocorticographic recordings from implanted electrodes were obtained in six patients with intractable epilepsy during a simple somatosensory detection task for near-threshold stimuli applied to the contralateral hand. Signal analyses were then conducted using a quantitative approach that employed two-way Hanning digital bandpass filters to compute running correlations across pairs of channels at various time epochs for each patient and each perception state across multiple bandwidths. Results Gamma coherence occurs in the primary somatosensory cortex approximately 150 to 300 milliseconds after contralateral hand stimuli that are perceived, but not for nonperceived stimuli, which did not differ in character/intensity or early somatosensory evoked potentials. Conclusion The results are consistent with the possible direct involvement of primary sensory cortex in elemental awareness and with a role for gamma coherence in conscious perception.

Cognitive and behavioral effects of lamotrigine and topiramate in healthy volunteers

Background: The relative cognitive and behavioral effects of lamotrigine (LTG) and topiramate (TPM) are unclear. Methods: The authors directly compared the cognitive and behavioral effects of LTG and TPM in 47 healthy adults using a double-blind, randomized crossover design with two 12-week treatment periods. During each treatment condition, subjects were titrated to receive either LTG or TPM at a target dose of 300 mg/day for each. Neuropsychological evaluation included 17 measures yielding 41 variables of cognitive function and subjective behavioral effects. Subjects were tested at the end of each antiepileptic drug (AED) treatment period and during two drug-free conditions (pretreatment baseline and 1 month following final AED withdrawal). Results: Direct comparison of the two AEDs revealed significantly better performance on 33 (80%) variables for LTG, but none for TPM. Even after adjustment for blood levels, performance was better on 19 (46%) variables for LTG, but none for TPM. Differences spanned both objective cognitive and subjective behavioral measures. Comparison of TPM to the non-drug average revealed significantly better performance for non-drug average on 36 (88%) variables, but none for TPM. Comparison of LTG to non-drug average revealed better performance on 7 (17%) variables for non-drug average and 4 (10%) variables for LTG. Conclusions: Lamotrigine produces significantly fewer untoward cognitive and behavioral effects compared to topiramate (TPM) at the dosages, titrations, and timeframes employed in this study. The dosages employed may not have been equivalent in efficacy. Future studies are needed to delineate the cognitive and behavioral effects of TPM at lower dosages.

Differential Cognitive Effects of Carbamazepine and Gabapentin

Summary: Purpose: The cognitive effects of the newer antiepileptic drugs (AEDs) compared with the older standard AEDs are uncertain.

Neuropsychological and neurophysiologic effects of carbamazepine and levetiracetam.

Background: The relative effects of levetiracetam (LEV) and carbamazepine (CBZ) on cognitive and neurophysiologic measures are uncertain. Methods: The effects of LEV and CBZ were compared in healthy adults using a randomized, double-blind, two-period crossover design. Outcome measures included 11 standard neuropsychological tests and the score from a cognitive-neurophysiologic test of attention and memory. Evaluations were conducted at screening, baseline pre-drug treatment, end of each maintenance phase (4 weeks), and end of each washout period after drug treatment. Results: A total of 28 adults (17 women) with mean age of 33 years (range 18 to 51) completed the study. Mean maintenance doses (±SD) were CBZ = 564 mg/day (110) and LEV = 2,000 mg/day (0). CBZ was adjusted to mid-range therapeutic level. Mean serum levels (±SD) were CBZ = 7.5 mcg/mL (1.5) and LEV = 32.2 mcg/mL (11.2). An overall composite score including all measures revealed worse effects for CBZ compared to LEV (p ≤ 0.001) in the primary analysis and for CBZ (p ≤ 0.001) and LEV (p ≤ 0.05) compared to non-drug in secondary analyses. Across the 34 individual variables, CBZ was worse than LEV on 44% (15/34); none favored CBZ. Compared to the non-drug average, CBZ was worse for 76% (26/34), and LEV was worse for 12% (4 of 34). Sensitivity and specificity of standard neuropsychological tests and the cognitive-neurophysiologic test were determined to direct future studies; detection was most accurate by the cognitive-neurophysiologic test. Conclusions: Levetiracetam produces fewer untoward neuropsychological and neurophysiologic effects than carbamazepine in monotherapy at the dosages and timeframes employed in this study.

Central Anticholinergic Hypersensitivity in Aging

Although neurochemical reductions in cholinergic systems have been found to occur during aging, such changes do not necessarily translate to functional deficits. The cognitive deficits of normal aging have been attributed in part to hypo-cholinergic function, but anticholinergic hypersensitivity in the elderly has not been systematically documented. To test the cholinergic hypothesis of aging, we investigated the effects of scopolamine on memory and attention in healthy young and elderly subjects. Treatments included intramuscular glycopyrrolate (0.0044 mg/kg) and scopolamine (0.002, 0.004, and 0.007 mg/kg) in a randomized double-blind design. The test battery included the Selective Reminding Task (SRT), Digit Span, Paired Associates Learning (PAL), Symbol Digit Modalities Test (SDMT), and the Continuous Performance Task. Elderly controls were more impaired at lower scopolamine doses than were the young on SRT, PAL, and SDMT. These results demonstrate anticholinergic hypersensitivity and are consistent with decremental changes in cholinergic status during normal aging. (J Geriatr Psychiatry Neurol 1992;5:72–77).

Physiology of somatosensory perception Cerebral lateralization and extinction

Objective: To demonstrate the effects of cerebral lateralization and temporal dynamics on somatosensory perception. Background: We postulated that perceptual thresholds for simple somatosensory stimuli would be less in the left than the right hand, and that a left/right asymmetry in extinction would exist in healthy right-handed subjects (but not in left-handed subjects). During the course of these experiments we also examined the controversy concerning the temporal dynamics of somatosensory perception. Methods: A total of 126 healthy subjects (age range, 6 to 73 years) participated in the study. Effects of handedness, age, vigilance, gaze, and temporal interval on somatosensory perception were examined in a series of experiments. Brief electric pulses were applied to the index finger of one or both hands. Results: Perceptual thresholds are lower in the left than the right hand of healthy right-handed subjects in a large cohort across a wide age range. Left-handed subjects have no overall asymmetry. Even after compensation for baseline threshold differences, single stimuli in right-handed subjects are perceived more readily in the left than the right hand, and left-hand targets are more difficult to mask. Leftward eye/head gaze lowers thresholds in both hands of right-handed subjects (compared with right or straight gaze). Extinction was consistently maximal when the mask followed the target by 50 to 100 msec. Conclusions: The findings demonstrate clearly that left/right perceptual thresholds for simple somatosensory stimuli are asymmetric in healthy right-handed subjects. Both central and peripheral asymmetries exist. The central asymmetry and gaze effects are consistent with right cerebral dominance for externally directed attention. Access of somatosensory stimuli to conscious awareness is delayed and particularly vulnerable to disruption at 50 to 100 msec after onset of the stimulus.

Lesions of nucleus basalis alter ChAT activity and EEG in rat frontal neocortex.

The EEG was recorded from frontal, parietal and visual cortices of sham-operated control rats and rats having ibotenic acid lesions of the nucleus basalis. Recordings were made during a period of rest and during stimulus-evoked desynchronization. Spectral power was determined using a Fast Fourier Transform routine; 3 artifact-free 4 sec epochs of resting activity and two 4 sec epochs of activated EEG were analyzed. Choline acetyltransferase activity (ChAT) was measured in each cortical area and was reduced in lesioned animals an average of 25% in frontal cortex, 19% in the parietal region and 10% in visual cortex. The percent of low frequency activity (1-12 Hz) in the frontal EEG was significantly greater in lesioned animals than in the control group during quiet rest; a significant correlation was found between ChAT activity and power in this band. Desynchronized activity was largely unaffected except for a reduction in 25-31 Hz activity in the frontal cortex of lesioned animals. EEG activity in both the parietal and visual areas was unchanged from control values.

Role of cerebral lateralization in control of immune processes in humans

Cerebral lateralization may be important in neural control of immune function. Animal studies have demonstrated differential effects of left and right brain lesions on immune function, but human studies are inconclusive. Here, we show that resections in the language dominant hemisphere of patients with epilepsy reduce lymphocytes, total T cells, and helper T cells. In contrast, resections in the language nondominant hemisphere increased the same cellular elements. T‐cell responses to mitogens and microbial antigens were not differentially affected. Left/right arm histamine skin response ratios were altered in patients with left cerebral epileptic focus, and flare skin responses were reduced by left cerebral resections in contrast with an increase after right cerebral resections. The findings demonstrate a differential role of the left and right cerebral hemispheres on immune functions in humans. Ann Neurol 2004

Physiology of perception Cortical stimulation and recording in humans

Objectives: 1) To determine the effect of stimulus train duration (TD) on sensory perception using direct stimulation of somatosensory and visual cortices. 2) To investigate the occurrence of evoked potentials in response to stimulation that is subthreshold for perception. Background: Studies of the mechanisms of conscious perception using direct cortical stimulation and recording techniques are rare. The clinical necessity to implant subdural electrode grids in epilepsy patients undergoing evaluation for surgery offers an opportunity to examine the role of stimulus parameters and evoked potentials in conscious perception. Methods: Subjects included epilepsy patients with grids over somatosensory or occipital cortex. Single pulses (100 microseconds) and stimulus trains were applied to electrodes, and thresholds for perception were found. Evoked potentials were recorded in response to peripheral stimulation at intensities at, above, and below sensory threshold. Results: During cortical stimulation, sensory threshold changed little for stimulus trains of 250 milliseconds and longer, but increased sharply as TD decreased below this level. Primary evoked activity was recorded in response to peripheral stimulations that were subthreshold for conscious perception. Conclusions: The results confirm a previous report of the effects of stimulus TD on sensory threshold. However, no motor responses occurred following somatosensory stimulation with short trains, as previously reported. The TD threshold pattern was similar in visual cortex. In agreement with the previous report, early components of the primary evoked response were not correlated with conscious sensory awareness.